chr17-44377095-G-C

Position:

chr17-44377095-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP7BP4BA1

This summary comes from the ClinGen Evidence Repository: After a comprehensive literature search of the intronic variant NM_000419.5(ITGA2B):c.2188-7C>G, no individuals with Glanzmann Thrombasthenia were reported with the variant. The variant has a high minor allele frequency of 0.4311 (6420/14892 alleles) in the East Asian population, which is higher than the ClinGen PD VCEP threshold (>0.0024), and therefore meets benign criterion (BA1). In silico predictor spliceAI revealed that the intronic mutation is not expected to impact splicing and a PhyloP score of 0.287 shows that the nucleotide position is not highly conserved (BP4, BP7). 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, BP4 and BP7 (PD VCEP specifications version 2.1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8602787/MONDO:0100326/011

Frequency

Genomes: 𝑓 0.39 ( 11438 hom., cov: 31)

Exomes 𝑓: 0.38 ( 100831 hom. )

Consequence

ITGA2B
NM_000419.5 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.005056

Clinical Significance

Benign reviewed by expert panel B:6

Conservation

PhyloP100: 0.709

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

BP7

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
ITGA2B	NM_000419.5 linkuse as main transcript	c.2188-7C>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000262407.6
ITGA2B	XM_011524749.2 linkuse as main transcript	c.2341-7C>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ITGA2B	XM_011524750.2 linkuse as main transcript	c.2341-7C>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
ITGA2B	ENST00000262407.6 linkuse as main transcript	c.2188-7C>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_000419.5	P1	P08514-1
ITGA2B	ENST00000648408.1 linkuse as main transcript	c.1619-7C>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ITGA2B	ENST00000592462.5 linkuse as main transcript	n.983-7C>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant	5

Frequencies

GnomAD3 genomes

AF:

0.387

AC:

58804

AN:

151814

Hom.:

11444

Cov.:

show subpopulations

Gnomad AFR

AF:

0.388

Gnomad AMI

AF:

0.412

Gnomad AMR

AF:

0.349

Gnomad ASJ

AF:

0.437

Gnomad EAS

AF:

0.446

Gnomad SAS

AF:

0.353

Gnomad FIN

AF:

0.436

Gnomad MID

AF:

0.320

Gnomad NFE

AF:

0.384

Gnomad OTH

AF:

0.362

GnomAD3 exomes

AF:

0.386

AC:

67631

AN:

175214

Hom.:

13056

AF XY:

0.382

AC XY:

35376

AN XY:

92514

show subpopulations

Gnomad AFR exome

AF:

0.385

Gnomad AMR exome

AF:

0.376

Gnomad ASJ exome

AF:

0.422

Gnomad EAS exome

AF:

0.431

Gnomad SAS exome

AF:

0.344

Gnomad FIN exome

AF:

0.438

Gnomad NFE exome

AF:

0.381

Gnomad OTH exome

AF:

0.364

GnomAD4 exome

AF:

0.377

AC:

530527

AN:

1407284

Hom.:

100831

Cov.:

AF XY:

0.375

AC XY:

261025

AN XY:

695440

show subpopulations

Gnomad4 AFR exome

AF:

0.367

Gnomad4 AMR exome

AF:

0.370

Gnomad4 ASJ exome

AF:

0.425

Gnomad4 EAS exome

AF:

0.426

Gnomad4 SAS exome

AF:

0.346

Gnomad4 FIN exome

AF:

0.430

Gnomad4 NFE exome

AF:

0.375

Gnomad4 OTH exome

AF:

0.380

GnomAD4 genome

AF:

0.387

AC:

58819

AN:

151932

Hom.:

11438

Cov.:

AF XY:

0.387

AC XY:

28704

AN XY:

74230

show subpopulations

Gnomad4 AFR

AF:

0.388

Gnomad4 AMR

AF:

0.349

Gnomad4 ASJ

AF:

0.437

Gnomad4 EAS

AF:

0.445

Gnomad4 SAS

AF:

0.351

Gnomad4 FIN

AF:

0.436

Gnomad4 NFE

AF:

0.384

Gnomad4 OTH

AF:

0.358

Alfa

AF:

0.388

Hom.:

2648

Bravo

AF:

0.380

Asia WGS

AF:

0.401

AC:

1403

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glanzmann thrombasthenia

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	Sep 07, 2023	After a comprehensive literature search of the intronic variant NM_000419.5(ITGA2B):c.2188-7C>G, no individuals with Glanzmann Thrombasthenia were reported with the variant. The variant has a high minor allele frequency of 0.4311 (6420/14892 alleles) in the East Asian population, which is higher than the ClinGen PD VCEP threshold (>0.0024), and therefore meets benign criterion (BA1). In silico predictor spliceAI revealed that the intronic mutation is not expected to impact splicing and a PhyloP score of 0.287 shows that the nucleotide position is not highly conserved (BP4, BP7). 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, BP4 and BP7 (PD VCEP specifications version 2.1). -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Glanzmann thrombasthenia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

2.5

DANN

Benign

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0051

dbscSNV1_RF

Benign

0.13

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

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