ClinVar Genomic variation as it relates to human health
NM_001006658.3(CR2):c.2298G>A (p.Trp766Ter)
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.
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(4); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001006658.3(CR2):c.2298G>A (p.Trp766Ter)
Variation ID: 473097 Accession: VCV000473097.49
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q32.2 1: 207474298 (GRCh38) [ NCBI UCSC ] 1: 207647643 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 May 26, 2018 Aug 4, 2024 Jan 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001006658.3:c.2298G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001006659.1:p.Trp766Ter nonsense NM_001877.5:c.2121G>A NP_001868.2:p.Trp707Ter nonsense NC_000001.11:g.207474298G>A NC_000001.10:g.207647643G>A NG_013006.1:g.24999G>A LRG_348:g.24999G>A LRG_348t1:c.2298G>A LRG_348p1:p.Trp766Ter - Protein change
- W766*, W707*
- Other names
- -
- Canonical SPDI
- NC_000001.11:207474297:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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0.00040 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
Trans-Omics for Precision Medicine (TOPMed) 0.00056
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00062
The Genome Aggregation Database (gnomAD) 0.00065
The Genome Aggregation Database (gnomAD), exomes 0.00075
Exome Aggregation Consortium (ExAC) 0.00097
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 | ||
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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. |
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CR2 | - | - |
GRCh38 GRCh37 |
643 | 750 |
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. |
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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 16, 2024 | RCV000542242.14 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Jul 25, 2023 | RCV000757139.39 |
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. |
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Pathogenic
(Aug 11, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885264.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
Comment:
The p.Trp766Ter variant, and c.1225+1G>C variant in compound heterozygous form, were previously reported in a 28-year old man with childhood history of recurrent respiratory tract … (more)
The p.Trp766Ter variant, and c.1225+1G>C variant in compound heterozygous form, were previously reported in a 28-year old man with childhood history of recurrent respiratory tract infections, intermittent 20 years of no health concerns, and recent persistent myalgias, fevers, sore throat, chronic diarrhea as well as recurrent respiratory tract infections, splenomegaly, hypogammaglobulinemia and no expression of CD21 surface protein (Thiel 2012). Additionally, no mRNA expression was found for p.Trp766Ter and carrier mother had reduced copy number of mRNA with this variant. Furthermore, no CD21 expression was found in vitro in 293T cells with p.Trp766Ter variant (Thiel 2012). This variant is listed in the genome Aggregation Database (gnomAD) with a European (Non-Finnish) population frequency of 0.15 percent (identified on 188 out of 126,374 chromosomes including 1 homozygote). Of note, Wentink et al. (2015) described an asymptomatic 13 year old individual with hypogammaglobulinemia and two loss-of-function CR2 variants. Thus, it is conceivable that individuals with milder immunological and clinical phenotype and homozygous loss-of function CR2 variants may have their data included in gnomAD database. (less)
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447832.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Isolated Pierre-Robin syndrome (present) , Microcephaly (present) , Hypotonia (present) , Global developmental delay (present) , Ventricular septal defect (present) , Immunodeficiency (present)
Sex: male
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Likely pathogenic
(Mar 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502249.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Likely pathogenic
(Jul 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000890334.3
First in ClinVar: Mar 19, 2019 Last updated: Aug 05, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies suggest a damaging effect on B-cell receptor stimulation (Thiel et al., 2012); This variant is associated with the following publications: (PMID: 30075290, Lougaris2020[Review Article], 22035880, 34426522, Tang2022[case report], 31345219) (less)
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Pathogenic
(Jan 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226722.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP4, PS3_supporting, PS4_supporting, PVS1
Number of individuals with the variant: 1
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Likely pathogenic
(Dec 15, 2020)
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criteria provided, single submitter
Method: clinical testing
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Immunodeficiency, common variable, 7
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002023388.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 16, 2024)
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criteria provided, single submitter
Method: clinical testing
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Immunodeficiency, common variable, 7
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000652484.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp766*) in the CR2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Trp766*) in the CR2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CR2 are known to be pathogenic (PMID: 26325596, 28499783). This variant is present in population databases (rs151093663, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with hypogammaglobulinemia (PMID: 22035880). ClinVar contains an entry for this variant (Variation ID: 473097). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CR2 function (PMID: 22035880). For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Nov 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000891875.26
First in ClinVar: Mar 31, 2019 Last updated: Aug 04, 2024 |
Number of individuals with the variant: 3
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Likely pathogenic
(Oct 23, 2019)
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no assertion criteria provided
Method: clinical testing
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Immunodeficiency, common variable, 7
Affected status: yes
Allele origin:
germline
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Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Accession: SCV001192647.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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The genetic structure of the Turkish population reveals high levels of variation and admixture. | Kars ME | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34426522 |
Deficiencies in the CD19 complex. | Wentink MWJ | Clinical immunology (Orlando, Fla.) | 2018 | PMID: 30075290 |
CD21 deficiency in 2 siblings with recurrent respiratory infections and hypogammaglobulinemia. | Rosain J | The journal of allergy and clinical immunology. In practice | 2017 | PMID: 28499783 |
CD21 and CD19 deficiency: Two defects in the same complex leading to different disease modalities. | Wentink MW | Clinical immunology (Orlando, Fla.) | 2015 | PMID: 26325596 |
Genetic CD21 deficiency is associated with hypogammaglobulinemia. | Thiel J | The Journal of allergy and clinical immunology | 2012 | PMID: 22035880 |
Text-mined citations for rs151093663 ...
HelpRecord last updated Aug 04, 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.