rs76066357

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1BP4

This summary comes from the ClinGen Evidence Repository: The NM_000419.5:c.439C>G variant in ITGA2B is a missense variant predicted to cause substitution of Leucine by Valine at amino acid 147 (p.Leu147Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.01420 (1822/128308 alleles) in the European (non-Finnish) population, which is higher than the ClinGen PD VCEP threshold (>0.0024) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.053, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2B function (BP4). This variant is also classified as Benign/Likely benign in ClinVar and was observed as part of a predisposition screen in an ostensibly healthy population by Illumina. In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PDVCEP: BA1 and BP4 (VCEP specifications version 2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA351291/MONDO:0100326/011

Frequency

Genomes: 𝑓 0.0092 ( 9 hom., cov: 33)

Exomes 𝑓: 0.012 ( 135 hom. )

Consequence

ITGA2B
NM_000419.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:7

Conservation

PhyloP100: 0.0980

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

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

BA1

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.439C>G	p.Leu147Val	missense_variant	Exon 4 of 30	ENST00000262407.6	NP_000410.2	P08514-1
ITGA2B	XM_011524749.2 link	c.592C>G	p.Leu198Val	missense_variant	Exon 4 of 29		XP_011523051.2	P08514
ITGA2B	XM_011524750.2 link	c.592C>G	p.Leu198Val	missense_variant	Exon 4 of 29		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6 link	c.439C>G	p.Leu147Val	missense_variant	Exon 4 of 30	1	NM_000419.5	ENSP00000262407.5		P08514-1
ITGA2B	ENST00000592944.1 link	n.124C>G		non_coding_transcript_exon_variant	Exon 1 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.00922

AC:

1403

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00234

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00870

Gnomad ASJ

AF:

0.00864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.00715

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0151

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.00915

AC:

2280

AN:

249236

AF XY:

0.00916

show subpopulations

Gnomad AFR exome

AF:

0.00231

Gnomad AMR exome

AF:

0.00622

Gnomad ASJ exome

AF:

0.0139

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00755

Gnomad NFE exome

AF:

0.0141

Gnomad OTH exome

AF:

0.0107

GnomAD4 exome

AF:

0.0116

AC:

17008

AN:

1461340

Hom.:

135

Cov.:

AF XY:

0.0116

AC XY:

8424

AN XY:

727004

show subpopulations

Gnomad4 AFR exome

AF:

0.00203

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.00644

AC:

288

AN:

44722

Gnomad4 ASJ exome

AF:

0.0126

AC:

330

AN:

26132

Gnomad4 EAS exome

AF:

0.0000252

AC:

AN:

39698

Gnomad4 SAS exome

AF:

0.00289

AC:

249

AN:

86254

Gnomad4 FIN exome

AF:

0.00697

AC:

369

AN:

52928

Gnomad4 NFE exome

AF:

0.0136

AC:

15093

AN:

1111978

Gnomad4 Remaining exome

AF:

0.00911

AC:

550

AN:

60382

Heterozygous variant carriers

1135

2269

3404

4538

5673

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

540

1080

1620

2160

2700

<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:

0.00920

AC:

1402

AN:

152366

Hom.:

Cov.:

AF XY:

0.00871

AC XY:

649

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00233

AC:

0.00233229

AN:

0.00233229

Gnomad4 AMR

AF:

0.00869

AC:

0.008686

AN:

0.008686

Gnomad4 ASJ

AF:

0.00864

AC:

0.00864055

AN:

0.00864055

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00311

AC:

0.00310559

AN:

0.00310559

Gnomad4 FIN

AF:

0.00715

AC:

0.00715361

AN:

0.00715361

Gnomad4 NFE

AF:

0.0151

AC:

0.0150803

AN:

0.0150803

Gnomad4 OTH

AF:

0.0114

AC:

0.0113529

AN:

0.0113529

Heterozygous variant carriers

147

221

294

368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome 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

Alfa

AF:

0.0126

Hom.:

Bravo

AF:

0.00867

TwinsUK

AF:

0.0129

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0131

AC:

113

ExAC

AF:

0.00928

AC:

1127

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0149

EpiControl

AF:

0.0153

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glanzmann thrombasthenia

Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Feb 02, 2023

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000419.5:c.439C>G variant in ITGA2B is a missense variant predicted to cause substitution of Leucine by Valine at amino acid 147 (p.Leu147Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.01420 (1822/128308 alleles) in the European (non-Finnish) population, which is higher than the ClinGen PD VCEP threshold (>0.0024) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.053, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2B function (BP4). This variant is also classified as Benign/Likely benign in ClinVar and was observed as part of a predisposition screen in an ostensibly healthy population by Illumina. In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1 and BP4 (VCEP specifications version 2). -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 10, 2020

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ITGA2B: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.050

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0041

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.0

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.99

REVEL

Benign

0.053

Sift

Benign

0.12

Sift4G

Benign

0.29

Polyphen

0.15

Vest4

0.22

MVP

0.60

MPC

1.2

ClinPred

0.0028

GERP RS

3.5

Varity_R

0.15

gMVP

0.63

Mutation Taster

=79/21

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over