rs76066357

Positions:

• chr17-44385686-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1 BP4

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 ENST00000262407.6 missense
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: 0.0980

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
ITGA2B	NM_000419.5	c.439C>G	p.Leu147Val	missense_variant	4/30	ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2	c.592C>G	p.Leu198Val	missense_variant	4/29		XP_011523051.2
ITGA2B	XM_011524750.2	c.592C>G	p.Leu198Val	missense_variant	4/29		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6	c.439C>G	p.Leu147Val	missense_variant	4/30	1	NM_000419.5	ENSP00000262407	P1
ITGA2B	ENST00000592944.1	n.124C>G		non_coding_transcript_exon_variant	1/6	5

Frequencies

GnomAD3 genomes AF: 0.00922 AC: 1403 AN: 152248 Hom.: 9 Cov.: 33

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

GnomAD3 exomes AF: 0.00915 AC: 2280 AN: 249236 Hom.: 25 AF XY: 0.00916 AC XY: 1240 AN XY: 135362

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 SAS exome AF: 0.00235

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.: 35 AF XY: 0.0116 AC XY: 8424 AN XY: 727004

Gnomad4 AFR exome AF: 0.00203

Gnomad4 AMR exome AF: 0.00644

Gnomad4 ASJ exome AF: 0.0126

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00289

Gnomad4 FIN exome AF: 0.00697

Gnomad4 NFE exome AF: 0.0136

Gnomad4 OTH exome AF: 0.00911

GnomAD4 genome AF: 0.00920 AC: 1402 AN: 152366 Hom.: 9 Cov.: 33 AF XY: 0.00871 AC XY: 649 AN XY: 74504

Gnomad4 AFR AF: 0.00233

Gnomad4 AMR AF: 0.00869

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00715

Gnomad4 NFE AF: 0.0151

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0126 Hom.: 16

Bravo AF: 0.00867

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0131 AC: 113

ExAC AF: 0.00928 AC: 1127

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0149

EpiControl AF: 0.0153

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, reviewed by expert panel	curation	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	Feb 02, 2023	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). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ITGA2B: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.053
Sift	Benign	0.12	T
Sift4G	Benign	0.29	T
Polyphen		0.15	B
Vest4		0.22
MVP		0.60
MPC		1.2
ClinPred		0.0028	T
GERP RS		3.5
Varity_R		0.15
gMVP		0.63

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

Other links and lift over

dbSNP: rs76066357; hg19: chr17-42463054; COSMIC: COSV99289415; COSMIC: COSV99289415;