rs2293649

Positions:

• chr2-172487375-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001394928.1(ITGA6):​c.2199C>T​(p.Asp733=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,612,818 control chromosomes in the GnomAD database, including 54,474 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5321 hom., cov: 33)
  • Exomes 𝑓: 0.24 (49153 hom.)
• Consequence: ITGA6 NM_001394928.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.04

Genes affected

ITGA6 (HGNC:6142): (integrin subunit alpha 6) The gene encodes a member of the integrin alpha chain family of proteins. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain that function in cell surface adhesion and signaling. The encoded preproprotein is proteolytically processed to generate light and heavy chains that comprise the alpha 6 subunit. This subunit may associate with a beta 1 or beta 4 subunit to form an integrin that interacts with extracellular matrix proteins including members of the laminin family. The alpha 6 beta 4 integrin may promote tumorigenesis, while the alpha 6 beta 1 integrin may negatively regulate erbB2/HER2 signaling. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

PDK1-AS1 (HGNC:40441): (PDK1 and ITGA6 antisense RNA 1)

LOC124900513 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-172487375-C-T is Benign according to our data. Variant chr2-172487375-C-T is described in ClinVar as [Benign]. Clinvar id is 332369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-172487375-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA6	NM_001394928.1	c.2199C>T	p.Asp733=	synonymous_variant	16/26	ENST00000442250.6
ITGA6	NM_000210.4	c.2082C>T	p.Asp694=	synonymous_variant	15/26	ENST00000684293.1
LOC124900513	XR_007087304.1	n.704-6354G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA6	ENST00000442250.6	c.2199C>T	p.Asp733=	synonymous_variant	16/26	5	NM_001394928.1
ITGA6	ENST00000684293.1	c.2082C>T	p.Asp694=	synonymous_variant	15/26		NM_000210.4	P3
PDK1-AS1	ENST00000442417.5	n.769-6354G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38456 AN: 152008 Hom.: 5314 Cov.: 33

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.339

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.551

Gnomad SAS AF: 0.419

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.253

GnomAD3 exomes AF: 0.306 AC: 76760 AN: 251228 Hom.: 13582 AF XY: 0.303 AC XY: 41186 AN XY: 135774

Gnomad AFR exome AF: 0.212

Gnomad AMR exome AF: 0.430

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.540

Gnomad SAS exome AF: 0.416

Gnomad FIN exome AF: 0.345

Gnomad NFE exome AF: 0.212

Gnomad OTH exome AF: 0.273

GnomAD4 exome AF: 0.244 AC: 356353 AN: 1460692 Hom.: 49153 Cov.: 33 AF XY: 0.248 AC XY: 180531 AN XY: 726742

Gnomad4 AFR exome AF: 0.218

Gnomad4 AMR exome AF: 0.423

Gnomad4 ASJ exome AF: 0.255

Gnomad4 EAS exome AF: 0.569

Gnomad4 SAS exome AF: 0.406

Gnomad4 FIN exome AF: 0.337

Gnomad4 NFE exome AF: 0.208

Gnomad4 OTH exome AF: 0.262

GnomAD4 genome AF: 0.253 AC: 38495 AN: 152126 Hom.: 5321 Cov.: 33 AF XY: 0.265 AC XY: 19687 AN XY: 74348

Gnomad4 AFR AF: 0.213

Gnomad4 AMR AF: 0.340

Gnomad4 ASJ AF: 0.256

Gnomad4 EAS AF: 0.551

Gnomad4 SAS AF: 0.417

Gnomad4 FIN AF: 0.352

Gnomad4 NFE AF: 0.209

Gnomad4 OTH AF: 0.257

Alfa AF: 0.226 Hom.: 6744

Bravo AF: 0.252

Asia WGS AF: 0.475 AC: 1649 AN: 3478

EpiCase AF: 0.218

EpiControl AF: 0.209

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Junctional epidermolysis bullosa with pyloric atresia Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.99
DANN	Benign	0.83

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

LitVar

Other links and lift over

dbSNP: rs2293649; hg19: chr2-173352103; COSMIC: COSV51219189; COSMIC: COSV51219189;