17-44378642-C-A

Variant names:

• chr17-44378642-C-A
• rs746091910
• NM_000419.5:c.1946+1G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000419.5(ITGA2B):​c.1946+1G>T variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ITGA2B NM_000419.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.63
• Publications: 0 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.8, offset of -35, new splice context is: gacGTatgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA2B	NM_000419.5	c.1946+1G>T		splice_donor_variant, intron_variant	Intron 19 of 29	ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2	c.2099+1G>T		splice_donor_variant, intron_variant	Intron 19 of 28		XP_011523051.2
ITGA2B	XM_011524750.2	c.2099+1G>T		splice_donor_variant, intron_variant	Intron 19 of 28		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6	c.1946+1G>T		splice_donor_variant, intron_variant	Intron 19 of 29	1	NM_000419.5	ENSP00000262407.5
ITGA2B	ENST00000648408.1	c.1376+1G>T		splice_donor_variant, intron_variant	Intron 15 of 24			ENSP00000498119.1
ITGA2B	ENST00000592462.5	n.741+1G>T		splice_donor_variant, intron_variant	Intron 8 of 14	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1414684 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 699102

African (AFR) AF: 0.00 AC: 0 AN: 32572

American (AMR) AF: 0.00 AC: 0 AN: 36776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25284

East Asian (EAS) AF: 0.00 AC: 0 AN: 37418

South Asian (SAS) AF: 0.00 AC: 0 AN: 80426

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087460

Other (OTH) AF: 0.00 AC: 0 AN: 58666

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	28
DANN	Benign	0.94
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		6.6
GERP RS		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.50		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs746091910; hg19: chr17-42456010;