17-44377095-G-C

Variant names:

• chr17-44377095-G-C
• rs850730
• NM_000419.5:c.2188-7C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BA1 BP7

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, 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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ITGA2B	NM_000419.5	c.2188-7C>G		splice_region_variant, intron_variant	Intron 21 of 29	ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2	c.2341-7C>G		splice_region_variant, intron_variant	Intron 21 of 28		XP_011523051.2
ITGA2B	XM_011524750.2	c.2341-7C>G		splice_region_variant, intron_variant	Intron 21 of 28		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6	c.2188-7C>G		splice_region_variant, intron_variant	Intron 21 of 29	1	NM_000419.5	ENSP00000262407.5
ITGA2B	ENST00000648408.1	c.1618-7C>G		splice_region_variant, intron_variant	Intron 17 of 24			ENSP00000498119.1
ITGA2B	ENST00000592462.5	n.983-7C>G		splice_region_variant, intron_variant	Intron 10 of 14	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

GnomAD2 exomes AF: 0.386 AC: 67631 AN: 175214 AF XY: 0.382

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 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 AC: 11928 AN: 32462

Gnomad4 AMR exome AF: 0.370 AC: 13775 AN: 37250

Gnomad4 ASJ exome AF: 0.425 AC: 10717 AN: 25190

Gnomad4 EAS exome AF: 0.426 AC: 15925 AN: 37360

Gnomad4 SAS exome AF: 0.346 AC: 27693 AN: 80130

Gnomad4 FIN exome AF: 0.430 AC: 21002 AN: 48790

Gnomad4 NFE exome AF: 0.375 AC: 405289 AN: 1081948

Gnomad4 Remaining exome AF: 0.380 AC: 22194 AN: 58448

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 AC: 0.387861 AN: 0.387861

Gnomad4 AMR AF: 0.349 AC: 0.348865 AN: 0.348865

Gnomad4 ASJ AF: 0.437 AC: 0.436636 AN: 0.436636

Gnomad4 EAS AF: 0.445 AC: 0.445068 AN: 0.445068

Gnomad4 SAS AF: 0.351 AC: 0.350728 AN: 0.350728

Gnomad4 FIN AF: 0.436 AC: 0.435524 AN: 0.435524

Gnomad4 NFE AF: 0.384 AC: 0.384255 AN: 0.384255

Gnomad4 OTH AF: 0.358 AC: 0.358428 AN: 0.358428

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 07, 2023

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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). -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glanzmann thrombasthenia 1 Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.5
DANN	Benign	0.53
Mutation Taster		=100/0	polymorphism (auto)

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;