17-44379780-A-G
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong
The NM_000419.5(ITGA2B):c.1787T>C(p.Ile596Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000645 in 1,613,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000066 ( 0 hom. )
Consequence
ITGA2B
NM_000419.5 missense
NM_000419.5 missense
Scores
9
7
3
Clinical Significance
Conservation
PhyloP100: 6.13
Genes affected
ITGA2B (HGNC:6138): (integrin subunit alpha 2b) This gene encodes a member of the integrin alpha chain family of proteins. The encoded preproprotein is proteolytically processed to generate light and heavy chains that associate through disulfide linkages to form a subunit of the alpha-IIb/beta-3 integrin cell adhesion receptor. This receptor plays a crucial role in the blood coagulation system, by mediating platelet aggregation. Mutations in this gene are associated with platelet-type bleeding disorders, which are characterized by a failure of platelet aggregation, including Glanzmann thrombasthenia. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
Variant 17-44379780-A-G is Pathogenic according to our data. Variant chr17-44379780-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 2900.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ITGA2B | NM_000419.5 | c.1787T>C | p.Ile596Thr | missense_variant | 18/30 | ENST00000262407.6 | |
ITGA2B | XM_011524749.2 | c.1940T>C | p.Ile647Thr | missense_variant | 18/29 | ||
ITGA2B | XM_011524750.2 | c.1940T>C | p.Ile647Thr | missense_variant | 18/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ITGA2B | ENST00000262407.6 | c.1787T>C | p.Ile596Thr | missense_variant | 18/30 | 1 | NM_000419.5 | P1 | |
ITGA2B | ENST00000648408.1 | c.1220T>C | p.Ile407Thr | missense_variant | 14/25 | ||||
ITGA2B | ENST00000592462.5 | n.582T>C | non_coding_transcript_exon_variant | 7/15 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000527 AC: 8AN: 151884Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000638 AC: 16AN: 250706Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135744
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GnomAD4 exome AF: 0.0000657 AC: 96AN: 1461712Hom.: 0 Cov.: 33 AF XY: 0.0000605 AC XY: 44AN XY: 727160
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GnomAD4 genome AF: 0.0000527 AC: 8AN: 151884Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74182
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Glanzmann thrombasthenia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 04, 2022 | ClinVar contains an entry for this variant (Variation ID: 2900). This missense change has been observed in individuals with clinical features of Glanzmann thrombasthenia (PMID: 9215749, 9734640, 20020534, 22513797, 25326637, 25373348). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs76811038, gnomAD 0.01%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 596 of the ITGA2B protein (p.Ile596Thr). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). - |
Pathogenic, reviewed by expert panel | curation | ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen | Nov 17, 2023 | The NM_000419.5(ITGA2B):c.1787T>C (p.Ile596Thr) missense variant has been reported in the homozygous state in at least 2 apparently unrelated individuals (PMID: 22513797, 20020534) and in the compound heterozygous state in 4 individuals (PMID: 9215749, 9734640, 34552732, 25373348). The second variants in these patients are c.3060+2T>C (classified Pathogenic by the PD-VCEP; without confirmation of trans phase), Glu355Lys (classified Pathogenic by the PD-VCEP; with confirmation of trans phase), c.2841+1G>T, and c.408G>C (latter two not considered here to avoid circularity) respectively (PM3_Strong). The proband from PMID: 22513797 meets criteria for PP4_Strong including mucocutaneous bleeding; abnormal platelet aggregometry in response to at least 2 agonist and normal response to ristocetin; absent surface expression of GPIIb-IIIa on flow cytometry; and full sequencing of ITGA2B and ITGB3. It was found to co-segregate with disease in 1 additional family member (PP1). Ile596Thr is reported in gnomAD v4.0.0 at a frequency of 0.00008305 (98/1179968 alleles) in the non-Finnish European population, below the PM2_supporting threshold of <0.0001. In summary, this variant is classified Pathogenic for autosomal recessive Glanzmann thrombasthenia. GT-specific codes applied: PP4_Strong, PM2_Supporting, PM3_Strong, PP1. (PD-VCEP specifications version 2) - |
Glanzmann thrombasthenia 1 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 1998 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 02, 2023 | Variant summary: ITGA2B c.1787T>C (p.Ile596Thr) results in a non-conservative amino acid change located in the Integrin alpha-2 domain (IPR013649) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 250706 control chromosomes (gnomAD). c.1787T>C has been reported in the literature as a biallelic genotype in individuals affected with Glanzmann thrombasthenia 1 (e.g. French_1997, Ruan_1998, Jallu_2010) and in one potential compound heterozygote (e.g. Lee_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9215749, 20020534, 25326637, 9734640). Two ClinVar submitters have assessed the variant since 2014, including one expert panel (ClinGen Platelet Disorders Variant Curation Expert Panel): the expert panel classified the variant as uncertain significance, and the other submitter classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of stability (P = 0.0055);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at