Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30096381, 22981119, 31053783, 30303587, 31661684, 33269433, 32991204, 32681043, 32860223, 33666369)
ClinVar Genomic variation as it relates to human health
NM_016366.3(CABP2):c.637+1G>T
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(19)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
19
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_016366.3(CABP2):c.637+1G>T
Variation ID: 597198 Accession: VCV000597198.52
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q13.2 11: 67519792 (GRCh38) [ NCBI UCSC ] 11: 67287263 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Nov 17, 2024 Mar 26, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_016366.3:c.637+1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001318496.2:c.655+1G>T splice donor NC_000011.10:g.67519792C>A NC_000011.9:g.67287263C>A NG_032982.1:g.8637G>T - Protein change
- -
- Other names
-
IVS6DS, G-T, +1
- Canonical SPDI
- NC_000011.10:67519791:C:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
Unknown function
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00077
The Genome Aggregation Database (gnomAD), exomes 0.00102
Exome Aggregation Consortium (ExAC) 0.00111
Trans-Omics for Precision Medicine (TOPMed) 0.00048
- Links
- Comment on variant
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| CABP2 | - | - |
GRCh38 GRCh37 |
104 | 122 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000733246.34 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
- | RCV001291207.2 | |
| Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Mar 26, 2024 | RCV000790515.18 | |
|
CABP2-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
May 17, 2024 | RCV003947951.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(May 14, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000861289.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Autosomal recessive nonsyndromic hearing loss 93
Affected status: yes
Allele origin:
unknown
|
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine
Accession: SCV000929845.1
First in ClinVar: Jul 28, 2019 Last updated: Jul 28, 2019 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jun 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 93
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostics Lab, Aalborg University Hospital
Accession: SCV001335281.1
First in ClinVar: Oct 10, 2020 Last updated: Oct 10, 2020 |
Indication for testing: Prelingual sensorineural, moderate and symmetrical hearing loss
Age: 0-9 years
Sex: male
Ethnicity/Population group: Caucasian
Geographic origin: Denmark
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 93
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Center for Statistical Genetics, Columbia University
Accession: SCV001622777.1
First in ClinVar: May 23, 2021 Last updated: May 23, 2021 |
Clinical Features:
Hearing impairment (present)
Sex: mixed
Ethnicity/Population group: Finnish European
Geographic origin: Finland
|
|
|
Pathogenic
(Jan 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001810803.3
First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023 |
Comment:
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: … (more)
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30096381, 22981119, 31053783, 30303587, 31661684, 33269433, 32991204, 32681043, 32860223, 33666369) (less)
|
|
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Pathogenic
(Jan 27, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 93
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018024.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001397367.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects a donor splice site in intron 6 of the CABP2 gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects a donor splice site in intron 6 of the CABP2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs149712664, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individual(s) with deafness (PMID: 22981119). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 597198). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 6 and introduces a new termination codon (PMID: 22981119). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002544579.16
First in ClinVar: Jul 09, 2022 Last updated: Oct 20, 2024 |
Comment:
CABP2: PM3:Strong, PP1:Strong, PVS1:Strong, PS3:Moderate, PM2:Supporting
Number of individuals with the variant: 7
|
|
|
Pathogenic
(Mar 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 93
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004176488.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The invariant splice donor c.637+1G>T variant in CABP2 gene has been observed homozygous / compound heterozygous state in individual(s) with deafness (Schrauwen et. al., 2012). … (more)
The invariant splice donor c.637+1G>T variant in CABP2 gene has been observed homozygous / compound heterozygous state in individual(s) with deafness (Schrauwen et. al., 2012). It has also been observed to segregate with disease in related individuals. Studies have shown that disruption of this splice site results in skipping of exon 6 and introduces a new termination codon (Schrauwen et. al., 2012). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (Buratti et. al., 2007). The c.637+1G>T variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.1% in gnomAD exomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant in CABP2 gene, the molecular diagnosis is not confirmed. (less)
Clinical Features:
Hearing impairment (present)
|
|
|
Pathogenic
(Sep 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004225740.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP1, PM3, PS4_moderate, PVS1_strong
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Mar 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 93
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806896.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
|
|
Pathogenic
(May 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197350.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(May 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 93
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center
Accession: SCV005397456.1
First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024 |
Comment:
This sequence variant is a single nucleotide substitution (G>T) at the +1 canonical donor splice site of the sixth of seven exons of the CABP2 … (more)
This sequence variant is a single nucleotide substitution (G>T) at the +1 canonical donor splice site of the sixth of seven exons of the CABP2 gene. The disruption of this donor site is expected to lead to the out of frame skipping of exon 6 resulting in the production of a truncated protein that lacks the calcium binding domains critical for calcium sensing by CABP2 (PMID: 22981119). This is a previously reported variant (ClinVar) that has been observed in individuals with hearing loss (PMID: 33666369, 32681043, 30303587). In addition, this variant segregated with hearing loss across multiple individuals in multiple families (PMID: 22981119, 32991204, 35150090, 33269433). This variant is present in 291 of 282,396 alleles (0.1%) in the gnomAD control population dataset. This variant is particularly common in the European Finnish population (0.3%); this relatively high minor allele frequency is attributed to stochastic demographic processes (PMID: 35150090). R, protein, and whole cell alysis confirms that this variant results in the skipping of exon 6, alters calcium affinity of the protein product, and disrupts calcium dependent ictivation of calcium channels (PMID: 22981119). Given this information, we consider this a pathogenic variant. ACMG Criteria: PP1, PS3, PVS1 (less)
|
|
|
Pathogenic
(Jul 06, 2019)
|
no assertion criteria provided
Method: research
|
Autosomal recessive nonsyndromic hearing loss 93
Affected status: yes
Allele origin:
germline
|
Laboratory of Prof. Karen Avraham, Tel Aviv University
Accession: SCV001337670.1
First in ClinVar: Jul 29, 2020 Last updated: Jul 29, 2020 |
Comment:
Recessive, compound heterozygous with NM_001318496.1: c.250G>A; congenital, variable SNHL
Number of individuals with the variant: 2
Ethnicity/Population group: Jewish mixed ancestries (Syria/Tunis, Turkey/Ashk)
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: research
|
non-syndromic autosomal recessive hearing loss
Affected status: yes
Allele origin:
inherited
|
University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV001479632.1
First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955407.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001970447.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
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Pathogenic
(Oct 05, 2012)
|
no assertion criteria provided
Method: literature only
|
DEAFNESS, AUTOSOMAL RECESSIVE 93
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000056718.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 26, 2024 |
Comment on evidence:
In affected members of 3 unrelated consanguineous Iranian families segregating autosomal recessive deafness (DFNB93; 614899), Schrauwen et al. (2012) identified homozygosity for a c.637+1G-T transversion … (more)
In affected members of 3 unrelated consanguineous Iranian families segregating autosomal recessive deafness (DFNB93; 614899), Schrauwen et al. (2012) identified homozygosity for a c.637+1G-T transversion (c.637+1G-T, NM_016366.2) at the 5-prime donor site of intron 6 of the CABP2 gene. The mutation segregated with disease in each family and was not found in 100 Iranian controls. Haplotype analysis indicated that it was likely a founder mutation inherited from an ancient common ancestor; the small size of the shared region suggested that the mutation might be hundreds or even thousands of years old. Analysis of cDNA prepared from transfected COS-7 cells revealed only a 177-bp PCR product, consistent with complete skipping of exon 6, which was predicted to result in a frameshift and premature termination at codon F164 (Phe164Serfs*4). Isothermal titration calorimetry of wildtype and F164X truncated CABP2 demonstrated an endothermic Ca(2+)-binding reaction for wildtype CABP2 that was weaker with the truncated protein, indicating altered Ca(2+) binding that might interfere with its role as a Ca(2+) sensor. Transfection studies in HEK293T cells showed that there was weaker suppression of the negative feedback regulation of Ca(v)1.3 Ca(2+) channels with mutant CABP2 than with wildtype; in addition, wildtype CABP2 significantly inhibited current density, whereas the mutant had no effect. In a 25-year-old man from sibship B of a large consanguineous Pakistani pedigree (PKDF1419), who had nonsyndromic moderate to severe deafness and an audiogram pattern consistent with DFNB93, Faridi et al. (2024) identified homozygosity for the previously reported splice site mutation (c.637+1G-T) in the CABP2 gene. The mutation segregated fully with disease in the family. In sibship A of the pedigree, an affected sister and brother with more severe to profound sensorineural deafness mapping to chromosome 5 (DFNB128) were homozygous for a mutation in the MAP3K1 gene (600982); thus the pedigree demonstrated intersibship familial locus heterogeneity. (less)
|
|
|
Pathogenic
(May 17, 2024)
|
no assertion criteria provided
Method: clinical testing
|
CABP2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004758150.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The CABP2 c.637+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant segregated with autosomal recessive hearing loss … (more)
The CABP2 c.637+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant segregated with autosomal recessive hearing loss in seven families with 15 affected and 11 unaffected individuals (Schrauwen. 2012. PubMed ID: 22981119; Ramzan. 2020. PubMed ID: 32681043; Sheyanth. 2021. PubMed ID: 33666369; Bharadwaj. 2022. PubMed ID: 35150090). This variant is reported in 0.33% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
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Comment:
Comment:
This sequence change affects a donor splice site in intron 6 of the CABP2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs149712664, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individual(s) with deafness (PMID: 22981119). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 597198). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 6 and introduces a new termination codon (PMID: 22981119). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Comment:
CABP2: PM3:Strong, PP1:Strong, PVS1:Strong, PS3:Moderate, PM2:Supporting
Comment:
The invariant splice donor c.637+1G>T variant in CABP2 gene has been observed homozygous / compound heterozygous state in individual(s) with deafness (Schrauwen et. al., 2012). It has also been observed to segregate with disease in related individuals. Studies have shown that disruption of this splice site results in skipping of exon 6 and introduces a new termination codon (Schrauwen et. al., 2012). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (Buratti et. al., 2007). The c.637+1G>T variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.1% in gnomAD exomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant in CABP2 gene, the molecular diagnosis is not confirmed.
Comment:
PP1, PM3, PS4_moderate, PVS1_strong
Comment:
This sequence variant is a single nucleotide substitution (G>T) at the +1 canonical donor splice site of the sixth of seven exons of the CABP2 gene. The disruption of this donor site is expected to lead to the out of frame skipping of exon 6 resulting in the production of a truncated protein that lacks the calcium binding domains critical for calcium sensing by CABP2 (PMID: 22981119). This is a previously reported variant (ClinVar) that has been observed in individuals with hearing loss (PMID: 33666369, 32681043, 30303587). In addition, this variant segregated with hearing loss across multiple individuals in multiple families (PMID: 22981119, 32991204, 35150090, 33269433). This variant is present in 291 of 282,396 alleles (0.1%) in the gnomAD control population dataset. This variant is particularly common in the European Finnish population (0.3%); this relatively high minor allele frequency is attributed to stochastic demographic processes (PMID: 35150090). R, protein, and whole cell alysis confirms that this variant results in the skipping of exon 6, alters calcium affinity of the protein product, and disrupts calcium dependent ictivation of calcium channels (PMID: 22981119). Given this information, we consider this a pathogenic variant. ACMG Criteria: PP1, PS3, PVS1
Comment:
Recessive, compound heterozygous with NM_001318496.1: c.250G>A; congenital, variable SNHL
Comment:
The CABP2 c.637+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant segregated with autosomal recessive hearing loss in seven families with 15 affected and 11 unaffected individuals (Schrauwen. 2012. PubMed ID: 22981119; Ramzan. 2020. PubMed ID: 32681043; Sheyanth. 2021. PubMed ID: 33666369; Bharadwaj. 2022. PubMed ID: 35150090). This variant is reported in 0.33% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
Unknown function
|
Molecular Diagnostics Lab, Aalborg University Hospital
Accession: SCV001335281.1
|
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||
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Unknown function
|
Center for Statistical Genetics, Columbia University
Accession: SCV001622777.1
|
|
Comment:
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30096381, 22981119, 31053783, 30303587, 31661684, 33269433, 32991204, 32681043, 32860223, 33666369)
Comment:
This sequence change affects a donor splice site in intron 6 of the CABP2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs149712664, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individual(s) with deafness (PMID: 22981119). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 597198). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 6 and introduces a new termination codon (PMID: 22981119). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Comment:
CABP2: PM3:Strong, PP1:Strong, PVS1:Strong, PS3:Moderate, PM2:Supporting
Comment:
The invariant splice donor c.637+1G>T variant in CABP2 gene has been observed homozygous / compound heterozygous state in individual(s) with deafness (Schrauwen et. al., 2012). It has also been observed to segregate with disease in related individuals. Studies have shown that disruption of this splice site results in skipping of exon 6 and introduces a new termination codon (Schrauwen et. al., 2012). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (Buratti et. al., 2007). The c.637+1G>T variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.1% in gnomAD exomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant in CABP2 gene, the molecular diagnosis is not confirmed.
Comment:
PP1, PM3, PS4_moderate, PVS1_strong
Comment:
This sequence variant is a single nucleotide substitution (G>T) at the +1 canonical donor splice site of the sixth of seven exons of the CABP2 gene. The disruption of this donor site is expected to lead to the out of frame skipping of exon 6 resulting in the production of a truncated protein that lacks the calcium binding domains critical for calcium sensing by CABP2 (PMID: 22981119). This is a previously reported variant (ClinVar) that has been observed in individuals with hearing loss (PMID: 33666369, 32681043, 30303587). In addition, this variant segregated with hearing loss across multiple individuals in multiple families (PMID: 22981119, 32991204, 35150090, 33269433). This variant is present in 291 of 282,396 alleles (0.1%) in the gnomAD control population dataset. This variant is particularly common in the European Finnish population (0.3%); this relatively high minor allele frequency is attributed to stochastic demographic processes (PMID: 35150090). R, protein, and whole cell alysis confirms that this variant results in the skipping of exon 6, alters calcium affinity of the protein product, and disrupts calcium dependent ictivation of calcium channels (PMID: 22981119). Given this information, we consider this a pathogenic variant. ACMG Criteria: PP1, PS3, PVS1
Comment:
Recessive, compound heterozygous with NM_001318496.1: c.250G>A; congenital, variable SNHL
Comment:
The CABP2 c.637+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant segregated with autosomal recessive hearing loss in seven families with 15 affected and 11 unaffected individuals (Schrauwen. 2012. PubMed ID: 22981119; Ramzan. 2020. PubMed ID: 32681043; Sheyanth. 2021. PubMed ID: 33666369; Bharadwaj. 2022. PubMed ID: 35150090). This variant is reported in 0.33% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Deafness DFNB128 Associated with a Recessive Variant of Human MAP3K1 Recapitulates Hearing Loss of Map3k1-Deficient Mice. | Faridi R | Genes | 2024 | PMID: 39062623 |
| Autosomal recessive nonsyndromic hearing impairment in two Finnish families due to the population enriched CABP2 c.637+1G>T variant. | Bharadwaj T | Molecular genetics & genomic medicine | 2022 | PMID: 35150090 |
| First reported CABP2-related non-syndromic hearing loss in Northern Europe. | Sheyanth IN | Molecular genetics & genomic medicine | 2021 | PMID: 33666369 |
| Homozygous mutations in Pakistani consanguineous families with prelingual nonsyndromic hearing loss. | Park HR | Molecular biology reports | 2020 | PMID: 33269433 |
| Spectrum of genes for inherited hearing loss in the Israeli Jewish population, including the novel human deafness gene ATOH1. | Brownstein Z | Clinical genetics | 2020 | DOI: 10.1111/cge.13817 |
| Screening Consanguineous Families for Hearing Loss Using the MiamiOtoGenes Panel. | Kannan-Sundhari A | Genetic testing and molecular biomarkers | 2020 | PMID: 32991204 |
| Spectrum of genetic variants in moderate to severe sporadic hearing loss in Pakistan. | Ramzan M | Scientific reports | 2020 | PMID: 32681043 |
| Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss. | Richard EM | Human mutation | 2019 | PMID: 30303587 |
| A mutation in CABP2, expressed in cochlear hair cells, causes autosomal-recessive hearing impairment. | Schrauwen I | American journal of human genetics | 2012 | PMID: 22981119 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CABP2 | - | - | - | - |
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Text-mined citations for rs149712664 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 19, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.
ClinGen staff contributed the HGVS expression for this variant.