17-44379752-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4BA1

This summary comes from the ClinGen Evidence Repository: The c.1815G>A variant is a synonymous (silent) variant (p.Pro605=) that is not predicted by SpliceAI to impact splicing (BP4). The highest population minor allele frequency in gnomAD v3.1.2 is 0.03782 (1565/41378 alleles) in African/African American population, which is higher than the ClinGen PD VCEP threshold (>0.0024) for BA1, and therefore meets this criterion (BA1). 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, BP7. (VCEP specifications version 2; date of approval 4/14/2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8602938/MONDO:0010119/011

Frequency

Genomes: 𝑓 0.016 ( 38 hom., cov: 32)

Exomes 𝑓: 0.0070 ( 75 hom. )

Consequence

ITGA2B
NM_000419.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:4

Conservation

PhyloP100: 0.348

Publications

10 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 -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 rank	MANE	Protein
ITGA2B	NM_000419.5 link	c.1815G>A	p.Pro605Pro	synonymous_variant	Exon 18 of 30	ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2 link	c.1968G>A	p.Pro656Pro	synonymous_variant	Exon 18 of 29		XP_011523051.2
ITGA2B	XM_011524750.2 link	c.1968G>A	p.Pro656Pro	synonymous_variant	Exon 18 of 29		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ITGA2B	ENST00000262407.6 link	c.1815G>A	p.Pro605Pro	synonymous_variant	Exon 18 of 30	1	NM_000419.5	ENSP00000262407.5
ITGA2B	ENST00000648408.1 link	c.1245G>A	p.Pro415Pro	synonymous_variant	Exon 14 of 25			ENSP00000498119.1
ITGA2B	ENST00000592462.5 link	n.610G>A		non_coding_transcript_exon_variant	Exon 7 of 15	5

Frequencies

GnomAD3 genomes

AF:

0.0155

AC:

2361

AN:

152000

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0378

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0120

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00757

Gnomad OTH

AF:

0.0172

GnomAD2 exomes

AF:

0.00755

AC:

1893

AN:

250740

AF XY:

0.00674

show subpopulations

Gnomad AFR exome

AF:

0.0383

Gnomad AMR exome

AF:

0.00735

Gnomad ASJ exome

AF:

0.0107

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000970

Gnomad NFE exome

AF:

0.00714

Gnomad OTH exome

AF:

0.00898

GnomAD4 exome

AF:

0.00700

AC:

10233

AN:

1461712

Hom.:

Cov.:

AF XY:

0.00678

AC XY:

4929

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.0403

AC:

1348

AN:

33478

American (AMR)

AF:

0.00852

AC:

381

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

300

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.000684

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

53244

Middle Eastern (MID)

AF:

0.0172

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00670

AC:

7453

AN:

1112008

Other (OTH)

AF:

0.00879

AC:

531

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

639

1278

1916

2555

3194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

296

592

888

1184

1480

<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:

0.0155

AC:

2364

AN:

152118

Hom.:

Cov.:

AF XY:

0.0145

AC XY:

1081

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0378

AC:

1569

AN:

41500

American (AMR)

AF:

0.0120

AC:

183

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00758

AC:

515

AN:

67984

Other (OTH)

AF:

0.0171

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

115

231

346

462

577

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00987

Hom.:

Bravo

AF:

0.0183

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00900

EpiControl

AF:

0.00871

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glanzmann thrombasthenia

Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 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. -

Jun 13, 2022

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.1815G>A variant is a synonymous (silent) variant (p.Pro605=) that is not predicted by SpliceAI to impact splicing (BP4). The highest population minor allele frequency in gnomAD v3.1.2 is 0.03782 (1565/41378 alleles) in African/African American population, which is higher than the ClinGen PD VCEP threshold (>0.0024) for BA1, and therefore meets this criterion (BA1). 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, BP7. (VCEP specifications version 2; date of approval 4/14/2022) -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

4.2

(source)

DANN

Benign

0.41

PhyloP100

0.35

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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