chr17-44377095-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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, intron

Scores

Splicing: ADA: 0.005056

Clinical Significance

Benign reviewed by expert panel B:7

Conservation

PhyloP100: 0.709

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

platelet-type bleeding disorder 16
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Glanzmann thrombasthenia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Glanzmann's thrombasthenia
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
Glanzmann thrombasthenia 1
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
autosomal dominant macrothrombocytopenia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ITGA2B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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	Effect	Exon rank	MANE	Protein	UniProt
ITGA2B	NM_000419.5 link	c.2188-7C>G	splice_region_variant, intron_variant	Intron 21 of 29	ENST00000262407.6	NP_000410.2	P08514-1
ITGA2B	XM_011524749.2 link	c.2341-7C>G	splice_region_variant, intron_variant	Intron 21 of 28		XP_011523051.2	P08514
ITGA2B	XM_011524750.2 link	c.2341-7C>G	splice_region_variant, intron_variant	Intron 21 of 28		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITGA2B	ENST00000262407.6 link	c.2188-7C>G	splice_region_variant, intron_variant	Intron 21 of 29	1	NM_000419.5	ENSP00000262407.5	P08514-1
ITGA2B	ENST00000648408.1 link	c.1618-7C>G	splice_region_variant, intron_variant	Intron 17 of 24			ENSP00000498119.1	A0A3B3IU79
ITGA2B	ENST00000592462.5 link	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.:

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

GnomAD2 exomes

AF:

0.386

AC:

67631

AN:

175214

AF XY:

0.382

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 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

African (AFR)

AF:

0.367

AC:

11928

AN:

32462

American (AMR)

AF:

0.370

AC:

13775

AN:

37250

Ashkenazi Jewish (ASJ)

AF:

0.425

AC:

10717

AN:

25190

East Asian (EAS)

AF:

0.426

AC:

15925

AN:

37360

South Asian (SAS)

AF:

0.346

AC:

27693

AN:

80130

European-Finnish (FIN)

AF:

0.430

AC:

21002

AN:

48790

Middle Eastern (MID)

AF:

0.351

AC:

2004

AN:

5706

European-Non Finnish (NFE)

AF:

0.375

AC:

405289

AN:

1081948

Other (OTH)

AF:

0.380

AC:

22194

AN:

58448

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

15729

31458

47186

62915

78644

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12908

25816

38724

51632

64540

<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:

0.387

AC:

58819

AN:

151932

Hom.:

11438

Cov.:

AF XY:

0.387

AC XY:

28704

AN XY:

74230

show subpopulations

African (AFR)

AF:

0.388

AC:

16059

AN:

41404

American (AMR)

AF:

0.349

AC:

5316

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.437

AC:

1516

AN:

3472

East Asian (EAS)

AF:

0.445

AC:

2301

AN:

5170

South Asian (SAS)

AF:

0.351

AC:

1687

AN:

4810

European-Finnish (FIN)

AF:

0.436

AC:

4600

AN:

10562

Middle Eastern (MID)

AF:

0.320

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.384

AC:

26114

AN:

67960

Other (OTH)

AF:

0.358

AC:

757

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1838

3676

5514

7352

9190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

570

1140

1710

2280

2850

<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:

0.388

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

LINK: link

Submissions by phenotype

Glanzmann thrombasthenia

Benign:3

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). -

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

(source)

DANN

Benign

0.53

PhyloP100

0.71

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over