ClinVar Genomic variation as it relates to human health
NM_000517.6(HBA2):c.95+2_95+6del
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000517.6(HBA2):c.95+2_95+6del
Variation ID: 375746 Accession: VCV000375746.24
- Type and length
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Deletion, 5 bp
- Location
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Cytogenetic: 16p13.3 16: 173005-173009 (GRCh38) [ NCBI UCSC ] 16: 223004-223008 (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 Mar 2, 2017 Sep 1, 2024 Aug 20, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000517.6:c.95+2_95+6del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_000517.6:c.95+2_95+6delTGAGG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000517.4:c.95+2_95+6delTGAGG NC_000016.10:g.173009_173013del NC_000016.9:g.223008_223012del NG_000006.1:g.33872_33876del NG_046165.1:g.2748_2752del NG_059186.1:g.1359_1363del NG_059271.1:g.5163_5167del LRG_1225:g.1359_1363del LRG_1240:g.5163_5167del LRG_1240t1:c.95+2_95+6del - Protein change
- Other names
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- Canonical SPDI
- NC_000016.10:173004:GAGGTGAGG:GAGG
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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HBA2 | - | - |
GRCh38 GRCh37 |
4 | 345 | |
LOC106804612 | - | - | - | GRCh38 | - | 282 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Feb 10, 2024 | RCV000417225.15 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Aug 20, 2024 | RCV001800665.21 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 24, 2022 | RCV002502452.8 |
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
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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
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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
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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
(Feb 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Heinz body anemia
alpha Thalassemia Hemoglobin H disease Erythrocytosis, familial, 7
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002813702.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Apr 18, 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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GeneDx
Accession: SCV002513024.2
First in ClinVar: May 21, 2022 Last updated: Mar 04, 2023 |
Comment:
Common variant reported in individuals of Mediterranean ethnicity with HbH disease (Orkin et al., 1981; Mesbah-Amroun et al., 2008; Farra et al., 2014; de la … (more)
Common variant reported in individuals of Mediterranean ethnicity with HbH disease (Orkin et al., 1981; Mesbah-Amroun et al., 2008; Farra et al., 2014; de la Fuent-Gonzalo et al., 2019); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Also denoted as IVS1-5nt and alpha-Hph due to alternative nomenclature; This variant is associated with the following publications: (PMID: 6946451, 15365991, 26771086, 31025160, 7151175, 25284125, 18473243, 23215864, 31589614, 29627922) (less)
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Pathogenic
(Dec 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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alpha Thalassemia
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557001.3
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2023 |
Comment:
The HBA2 c.95+2_95+6del variant is classified as Pathogenic (PVS1, PS4, PP4) The HBA2 c.95+2_95+6del variant is located in a splice donor region. Computational predictions support … (more)
The HBA2 c.95+2_95+6del variant is classified as Pathogenic (PVS1, PS4, PP4) The HBA2 c.95+2_95+6del variant is located in a splice donor region. Computational predictions support a deleterious effect on splicing and a likely disruption of the protein reading frame and non-sense mediated decay of the resulting protein product (PVS1). This pentanucleotide HBA2:c.95+2_95+6delTGAGG deletion occurs within the 5' splice junction of the first intervening sequence, preventing normal RNA splicing. This mutation is listed on the Haemoglobin Variant Database as an alpha thalassaemia mutation (PMID: 7151175) (PS4). Present in numerous internal database patients as per alamut with consistent symptoms of alpha thalassaemia carrier. No functional studies performed. The clinical features of this case are highly specific for HBA1/2, and this patient has a well-defined syndrome with little overlap with other clinical presentations (PP4). Variants in HBA1/2 are highly specific for alpha thalassaemia. The variant has been reported in dbSNP (rs41474145) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 375746). It has been reported in HGMD (CD810004). (less)
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Pathogenic
(Sep 30, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002047269.3
First in ClinVar: Jan 03, 2022 Last updated: Jan 06, 2024 |
Comment:
The c.95+2_95+6delTGAGG pathogenic variant in the alpha2-globin (HBA2) gene is the deletion of nucleotides 2 to 6 (TGAGG) of intron 1. This deletion occurs in … (more)
The c.95+2_95+6delTGAGG pathogenic variant in the alpha2-globin (HBA2) gene is the deletion of nucleotides 2 to 6 (TGAGG) of intron 1. This deletion occurs in the splice-donor site and prevents normal splicing of the alpha2-globin mRNA (see , and PMIDs: 6946451 (1981), 7151175 (1982), and 20507641 (2010)), and has been reported in individuals affected with alpha thalassemia in the published literature (PMIDs: 6946451 (1981), 7151175 (1982), 15365991 (2004), and 29115104 (2018)). An in vitro study reports no functional alpha-globin protein is synthesized from the mutant alpha2-globin allele (PMID: 7151175 (1982)). (less)
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Pathogenic
(Feb 10, 2024)
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criteria provided, single submitter
Method: clinical testing
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alpha Thalassemia
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848829.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The c.95+2_95+6del variant in HBA2 is a common pathogenic variant for alpha thalassemia in the Mediterranean region (Felber 1982 PMID: 7151175, Lacerra 2004 PMID: 15365991, … (more)
The c.95+2_95+6del variant in HBA2 is a common pathogenic variant for alpha thalassemia in the Mediterranean region (Felber 1982 PMID: 7151175, Lacerra 2004 PMID: 15365991, Orkin 1981 PMID: 6946451, HbVar database: https://globin.bx.psu.edu/hbvar/menu.html; HbVarID:1065). This variant has been reported by other clinical laboratories in ClinVar (Variation ID 375746) and was absent from large population studies (gnomAD, v.3.1.2). This deletion affects the canonical splice site position (+2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Biallelic loss of function of the HBA2 gene is an established disease mechanism in autosomal recessive alpha thalassemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive alpha thalassemia. ACMG/AMP Criteria applied: PVS1_Strong, PM3_Strong, PM2_supporting. (less)
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Pathogenic
(Jul 31, 2024)
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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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005090174.1
First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 |
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Pathogenic
(Aug 20, 2024)
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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: SCV001160097.6
First in ClinVar: Feb 10, 2020 Last updated: Sep 01, 2024 |
Comment:
The HBA2 c.95+2_95+6del variant (rs41474145, HbVar ID: 1065, also known as alpha-thal-2 (-5nt) and IVS1 (-5nt)) is a common pathogenic alpha thalassemia variant and has … (more)
The HBA2 c.95+2_95+6del variant (rs41474145, HbVar ID: 1065, also known as alpha-thal-2 (-5nt) and IVS1 (-5nt)) is a common pathogenic alpha thalassemia variant and has been reported in heterozygous individuals with mild hypochromic microcytic anemia or silent carriers and in compound heterozygous individuals with alpha-thalassemia trait (Alhuthali 2023, Lacerra 2004, Orkin 1981, see HbVar link). This variant disrupts the canonical splice donor site of intron 1 and alters splicing (Felber 1982, Orkin 1981). Based on the information available, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Alhuthali HM et al. Molecular patterns of alpha-thalassemia in the kingdom of Saudi Arabia: identification of prevalent genotypes and regions with high incidence. Thromb J. 2023 Nov 10;21(1):115. PMID: 37950286. Felber BK et al. Abnormal RNA splicing causes one form of alpha thalassemia. Cell. 1982 Jul;29(3):895-902. PMID: 7151175. Lacerra G et al. Sequence variations of the alpha-globin genes: scanning of high CG content genes with DHPLC and DG-DGGE. Hum Mutat. 2004 Oct;24(4):338-49. PMID: 15365991. Orkin SH et al. Mutation in an intervening sequence splice junction in man. Proc Natl Acad Sci U S A. 1981 Aug;78(8):5041-5. PMID: 6946451. (less)
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Pathogenic
(Aug 17, 2017)
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no assertion criteria provided
Method: clinical testing
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Alpha thalassemia
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002093843.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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alpha Thalassemia
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000503055.2
First in ClinVar: Mar 02, 2017 Last updated: Oct 01, 2022 |
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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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Alpha-Thalassemia. | Adam MP | - | 2024 | PMID: 20301608 |
Severe α-Thalassemia Due to Compound Heterozygosity for Hb Adana (α59 Gly>Asp) (HBA1: c.179G > A) and Codon 127 (A > T) (HBA2: c.382A > T) in an Iranian Family. | Azimi A | Hemoglobin | 2020 | PMID: 32498570 |
Molecular Basis of α-Thalassemia in Iran. | Valaei A | Iranian biomedical journal | 2018 | PMID: 29115104 |
The genetic basis of asymptomatic codon 8 frame-shift (HBB:c25_26delAA) β(0) -thalassaemia homozygotes. | Jiang Z | British journal of haematology | 2016 | PMID: 26771086 |
Alpha-thalassaemia. | Harteveld CL | Orphanet journal of rare diseases | 2010 | PMID: 20507641 |
Molecular basis of alpha-thalassemia in Algeria. | Mesbah-Amroun H | Hemoglobin | 2008 | PMID: 18473243 |
Sequence variations of the alpha-globin genes: scanning of high CG content genes with DHPLC and DG-DGGE. | Lacerra G | Human mutation | 2004 | PMID: 15365991 |
Abnormal RNA splicing causes one form of alpha thalassemia. | Felber BK | Cell | 1982 | PMID: 7151175 |
Mutation in an intervening sequence splice junction in man. | Orkin SH | Proceedings of the National Academy of Sciences of the United States of America | 1981 | PMID: 6946451 |
Text-mined citations for rs41474145 ...
HelpRecord last updated Sep 29, 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.