2-172427798-G-A

Position:

chr2-172427798-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The NM_000210.4(ITGA6):c.10G>A(p.Ala4Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,594,758 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

ITGA6
NM_000210.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.830

Variant links:

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]

ITGA6 links:

ENSG00000226963 (HGNC:):

ENSG00000226963 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.006976247).

BP6

Variant 2-172427798-G-A is Benign according to our data. Variant chr2-172427798-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 332355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0013 (198/152112) while in subpopulation AFR AF= 0.00455 (189/41534). AF 95% confidence interval is 0.00402. There are 0 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITGA6	NM_001394928.1 link	c.10G>A	p.Ala4Thr	missense_variant	1/26	ENST00000442250.6	NP_001381857.1
ITGA6	NM_000210.4 link	c.10G>A	p.Ala4Thr	missense_variant	1/26	ENST00000684293.1	NP_000201.2	P23229-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGA6	ENST00000442250.6 link	c.10G>A	p.Ala4Thr	missense_variant	1/26	5	NM_001394928.1	ENSP00000406694.1		P23229-1
ITGA6	ENST00000684293.1 link	c.10G>A	p.Ala4Thr	missense_variant	1/26		NM_000210.4	ENSP00000508249.1		P23229-2

Frequencies

GnomAD3 genomes

AF:

0.00130

AC:

197

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00454

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000320

AC:

AN:

218732

Hom.:

AF XY:

0.000314

AC XY:

AN XY:

121052

show subpopulations

Gnomad AFR exome

AF:

0.00488

Gnomad AMR exome

AF:

0.000192

Gnomad ASJ exome

AF:

0.000108

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000356

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000207

Gnomad OTH exome

AF:

0.000381

GnomAD4 exome

AF:

0.000148

AC:

213

AN:

1442646

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

104

AN XY:

717414

show subpopulations

Gnomad4 AFR exome

AF:

0.00504

Gnomad4 AMR exome

AF:

0.000236

Gnomad4 ASJ exome

AF:

0.0000390

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000239

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000543

Gnomad4 OTH exome

AF:

0.000487

GnomAD4 genome

AF:

0.00130

AC:

198

AN:

152112

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00455

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000196

Hom.:

Bravo

AF:

0.00161

ESP6500AA

AF:

0.00481

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000489

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

- -

Junctional epidermolysis bullosa with pyloric atresia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.097

.;T;.;.

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.76

T;T;T;T

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.0070

T;T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.0

N;N;N;N

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.59

N;N;N;N

REVEL

Benign

0.25

Sift

Uncertain

0.017

D;D;D;D

Sift4G

Benign

0.099

T;T;T;T

Polyphen

0.012

B;.;.;.

Vest4

0.16

MVP

0.85

MPC

0.39

ClinPred

0.026

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.064

gMVP

0.75

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over