chr17-44377095-G-C

Position:

• chr17-44377095-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP7 BP4 BA1

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:7
• Conservation: PhyloP100: 0.709

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 -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: 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.2188-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2	c.2341-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_011523051.2
ITGA2B	XM_011524750.2	c.2341-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6	c.2188-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000419.5	ENSP00000262407	P1
ITGA2B	ENST00000648408.1	c.1619-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant				ENSP00000498119
ITGA2B	ENST00000592462.5	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.: 31

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

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.: 33 AF XY: 0.375 AC XY: 261025 AN XY: 695440

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.: 31 AF XY: 0.387 AC XY: 28704 AN XY: 74230

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:7

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Benign:3

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). -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

Other links and lift over

dbSNP: rs850730; hg19: chr17-42454463; COSMIC: COSV52231019; COSMIC: COSV52231019;