rs76811038

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP4_StrongPP1PM2_SupportingPM3_Strong

This summary comes from the ClinGen Evidence Repository: 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) LINK:https://erepo.genome.network/evrepo/ui/classification/CA115846/MONDO:0100326/011

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

ITGA2B
NM_000419.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:6

Conservation

PhyloP100: 6.13

Publications

10 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: Pathogenic. The variant received 10 ACMG points.

PM2

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

PM3

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

PP1

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

PP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA2B	NM_000419.5 link	c.1787T>C	p.Ile596Thr	missense_variant	Exon 18 of 30	ENST00000262407.6	NP_000410.2	P08514-1
ITGA2B	XM_011524749.2 link	c.1940T>C	p.Ile647Thr	missense_variant	Exon 18 of 29		XP_011523051.2	P08514
ITGA2B	XM_011524750.2 link	c.1940T>C	p.Ile647Thr	missense_variant	Exon 18 of 29		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITGA2B	ENST00000262407.6 link	c.1787T>C	p.Ile596Thr	missense_variant	Exon 18 of 30	1	NM_000419.5	ENSP00000262407.5	P08514-1
ITGA2B	ENST00000648408.1 link	c.1217T>C	p.Ile406Thr	missense_variant	Exon 14 of 25			ENSP00000498119.1	A0A3B3IU79
ITGA2B	ENST00000592462.5 link	n.582T>C		non_coding_transcript_exon_variant	Exon 7 of 15	5

Frequencies

GnomAD3 genomes

AF:

0.0000527

AC:

AN:

151884

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000638

AC:

AN:

250706

AF XY:

0.0000442

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000133

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000657

AC:

AN:

1461712

Hom.:

Cov.:

AF XY:

0.0000605

AC XY:

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000827

AC:

AN:

1112008

Other (OTH)

AF:

0.0000166

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000527

AC:

AN:

151884

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74182

show subpopulations

African (AFR)

AF:

0.0000484

AC:

AN:

41350

American (AMR)

AF:

0.00

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5138

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000883

AC:

AN:

67960

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

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:

0.0000792

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glanzmann thrombasthenia

Pathogenic:2

Nov 17, 2023

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

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) -

Jul 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). This variant is present in population databases (rs76811038, gnomAD 0.01%). 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. ClinVar contains an entry for this variant (Variation ID: 2900). 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"). For these reasons, this variant has been classified as Pathogenic. -

Glanzmann thrombasthenia 1

Pathogenic:2

Jun 02, 2023

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 01, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Dec 18, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20020534, 22513797, 25326637, 9734640, 37647632, 9215749, 34552732, 25373348) -

ITGA2B-related disorder

Pathogenic:1

Jul 02, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ITGA2B c.1787T>C variant is predicted to result in the amino acid substitution p.Ile596Thr. This variant has been reported in the compound heterozygous state and homozygous states in two patients with Glanzmann’s thrombasthenia (French et al. 1997. PubMed ID: 9215749). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic by the ClinGen Platelet Disorders Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/2900/). We interpret this variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.069

MutationAssessor

Pathogenic

3.5

PhyloP100

6.1

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-4.4

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.92

MutPred

0.95

Loss of stability (P = 0.0055);

MVP

0.87

MPC

1.1

ClinPred

0.57

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.87

Mutation Taster

=38/62

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over