2-160107777-C-G

Position:

• chr2-160107777-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000888.5(ITGB6):​c.2170G>C​(p.Val724Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,613,952 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00083 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (3 hom.)
• Consequence: ITGB6 NM_000888.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.196

Genes affected

ITGB6 (HGNC:6161): (integrin subunit beta 6) This gene encodes a protein that is a member of the integrin superfamily. Members of this family are adhesion receptors that function in signaling from the extracellular matrix to the cell. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. The encoded protein forms a dimer with an alpha v chain and this heterodimer can bind to ligands like fibronectin and transforming growth factor beta 1. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010565132).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000834 (127/152288) while in subpopulation NFE AF= 0.00132 (90/68038). AF 95% confidence interval is 0.0011. There are 0 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITGB6	NM_000888.5	c.2170G>C	p.Val724Leu	missense_variant	14/15	ENST00000283249.7	NP_000879.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGB6	ENST00000283249.7	c.2170G>C	p.Val724Leu	missense_variant	14/15	1	NM_000888.5	ENSP00000283249	P1

Frequencies

GnomAD3 genomes AF: 0.000835 AC: 127 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000935 AC: 235 AN: 251350 Hom.: 0 AF XY: 0.000928 AC XY: 126 AN XY: 135830

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00151

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00166 AC: 2421 AN: 1461664 Hom.: 3 Cov.: 30 AF XY: 0.00161 AC XY: 1171 AN XY: 727144

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00146

Gnomad4 NFE exome AF: 0.00201

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.000834 AC: 127 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74450

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000817 Hom.: 0

Bravo AF: 0.000733

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.000906 AC: 110

EpiCase AF: 0.00109

EpiControl AF: 0.00124

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	3.8
DANN	Benign	0.59
DEOGEN2	Benign	0.15	T;.;.;.;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.83	.;T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.011	T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.30	N;.;.;.;N
MutationTaster	Benign	0.94	N;N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	1.3	N;.;N;N;N
REVEL	Benign	0.18
Sift	Benign	1.0	T;.;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0010	B;.;B;.;B
Vest4		0.28
MVP		0.30
MPC		0.027
ClinPred		0.018	T
GERP RS		3.0
Varity_R		0.064
gMVP		0.31

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: rs146397669; hg19: chr2-160964288;