17-44374449-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BS1BP2BP4

This summary comes from the ClinGen Evidence Repository: The ITGA2B missense variant c.2965G>A (p.Ala989Thr) has been observed in at least two probands with GT (PMIDs: 25539746, 15099289) however it was in cis with the pathogenic variant Val982Met.Expression in COS-7 cells did not reduce αIIbβ3 surface expression, however functionality was not assessed. Computational evidence suggest no impact on the gene/gene product, with a REVEL score of 0.13. In summary, this variant meets criteria to be classified as Likely Benign for GT. GT-specific criteria applied: BP2 and BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8602498/MONDO:0010119/011

Frequency

Genomes: 𝑓 0.00066 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00046 ( 3 hom. )

Consequence

ITGA2B
NM_000419.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:3B:6

Conservation

PhyloP100: 1.79

Publications

11 publications found

Variant links:

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]

ITGA2B Gene-Disease associations (from GenCC):

platelet-type bleeding disorder 16
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Glanzmann thrombasthenia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Glanzmann's thrombasthenia
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
Glanzmann thrombasthenia 1
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
autosomal dominant macrothrombocytopenia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ITGA2B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP2

For more information check the summary or visit ClinGen Evidence Repository.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000419.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA2B	NM_000419.5	MANE Select	c.2965G>A	p.Ala989Thr	missense	Exon 29 of 30	NP_000410.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ITGA2B	ENST00000262407.6	TSL:1 MANE Select	c.2965G>A	p.Ala989Thr	missense	Exon 29 of 30	ENSP00000262407.5
ITGA2B	ENST00000592462.5	TSL:5	n.2664G>A		non_coding_transcript_exon	Exon 15 of 15
ITGA2B	ENST00000648408.1		c.2373+210G>A		intron	N/A	ENSP00000498119.1

Frequencies

GnomAD3 genomes

AF:

0.000670

AC:

102

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000597

AC:

150

AN:

251386

AF XY:

0.000611

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000686

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.000460

AC:

672

AN:

1461854

Hom.:

Cov.:

AF XY:

0.000476

AC XY:

346

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33480

American (AMR)

AF:

0.00165

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000209

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.0132

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000387

AC:

430

AN:

1112002

Other (OTH)

AF:

0.000878

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

136

182

227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000663

AC:

101

AN:

152284

Hom.:

Cov.:

AF XY:

0.000672

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41558

American (AMR)

AF:

0.00333

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68010

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000572

Hom.:

Bravo

AF:

0.000903

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000651

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00147

EpiControl

AF:

0.00130

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glanzmann thrombasthenia

Uncertain:2Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 989 of the ITGA2B protein (p.Ala989Thr). This variant is present in population databases (rs78165611, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Glanzmann thrombasthenia who also carried additional ITGA2B variants that may account for their clinical status (PMID: 15099289, 20020534, 25539746). ClinVar contains an entry for this variant (Variation ID: 417951). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ITGA2B protein function. Experimental studies have shown that this missense change does not substantially affect ITGA2B function (PMID: 15099289). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Jun 16, 2020

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The ITGA2B missense variant c.2965G>A (p.Ala989Thr) has been observed in at least two probands with GT (PMIDs: 25539746, 15099289) however it was in cis with the pathogenic variant Val982Met.Expression in COS-7 cells did not reduce Î±IIbÎ²3 surface expression, however functionality was not assessed. Computational evidence suggest no impact on the gene/gene product, with a REVEL score of 0.13. In summary, this variant meets criteria to be classified as Likely Benign for GT. GT-specific criteria applied: BP2 and BP4.

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ITGA2B: BP4

Glanzmann thrombasthenia;C5442010:Platelet-type bleeding disorder 16

Uncertain:1

Feb 15, 2016

Division of Human Genetics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

not specified

Benign:1

Nov 04, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ITGA2B c.2965G>A (p.Ala989Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0006 in 251386 control chromosomes, predominantly at a frequency of 0.0014 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ITGA2B causing ITGA2B-Related Disorders, allowing no conclusion about variant significance. c.2965G>A has been reported in the literature in individuals affected with ITGA2B-Related Disorders (Marconi_2023, Jallu_2010, Leine_2017, Sanchez-Guiu_2014). These report(s) do not provide unequivocal conclusions about association of the variant with ITGA2B-Related Disorders. A co-occurrence with another pathogenic variant has been reported (ITGA2B c.1612G>T, p.Glu538*), providing supporting evidence for a benign role (Sanchez-Guiu_2014). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Nurden_2004). This variant is also known as p.Ala958Thr. The following publications have been ascertained in the context of this evaluation (PMID: 20020534, 28748566, 36519321, 25539746, 15099289). ClinVar contains an entry for this variant (Variation ID: 417951). Based on the evidence outlined above, the variant was classified as likely benign.

Platelet-type bleeding disorder 16;CN300358:Glanzmann thrombasthenia 1

Benign:1

Nov 08, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

ITGA2B-related disorder

Benign:1

Feb 01, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.044

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.76

M_CAP

Benign

0.035

MetaRNN

Benign

0.082

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.9

PhyloP100

1.8

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.1

REVEL

Benign

0.13

Sift

Uncertain

0.017

Sift4G

Benign

0.22

Polyphen

0.017

Vest4

0.086

MVP

0.59

MPC

0.28

ClinPred

0.043

GERP RS

5.0

Varity_R

0.31

gMVP

0.35

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.20

Position offset: -28

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over