rs146278697

Positions:

chr10-74090083-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_014000.3(VCL):c.1237G>A(p.Ala413Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000575 in 1,614,160 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 2 hom. )

Consequence

VCL
NM_014000.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.10

Variant links:

Genes affected

VCL (HGNC:12665): (vinculin) Vinculin is a cytoskeletal protein associated with cell-cell and cell-matrix junctions, where it is thought to function as one of several interacting proteins involved in anchoring F-actin to the membrane. Defects in VCL are the cause of cardiomyopathy dilated type 1W. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Multiple alternatively spliced transcript variants have been found for this gene, but the biological validity of some variants has not been determined. [provided by RefSeq, Jul 2008]

VCL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VCL. . Gene score misZ 2.7082 (greater than the threshold 3.09). Trascript score misZ 4.2375 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, hypertrophic cardiomyopathy 15, hypertrophic cardiomyopathy, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1W.

BP4

Computational evidence support a benign effect (MetaRNN=0.03369975).

BP6

Variant 10-74090083-G-A is Benign according to our data. Variant chr10-74090083-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 45575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74090083-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCL	NM_014000.3 linkuse as main transcript	c.1237G>A	p.Ala413Thr	missense_variant	10/22	ENST00000211998.10	NP_054706.1
VCL	NM_003373.4 linkuse as main transcript	c.1237G>A	p.Ala413Thr	missense_variant	10/21		NP_003364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10 linkuse as main transcript	c.1237G>A	p.Ala413Thr	missense_variant	10/22	1	NM_014000.3	ENSP00000211998		P18206-1

Frequencies

GnomAD3 genomes

AF:

0.000421

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000808

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000298

AC:

AN:

251402

Hom.:

AF XY:

0.000302

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000510

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000591

AC:

864

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000571

AC XY:

415

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000728

Gnomad4 OTH exome

AF:

0.000563

GnomAD4 genome

AF:

0.000420

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000809

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000584

Hom.:

Bravo

AF:

0.000408

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000239

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2021	This variant is associated with the following publications: (PMID: 30847666, 26406308, 28750076, 28771489, 28087426, 24503780, 23861362) -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 29, 2014

p.Ala413Thr in exon 10 of VCL: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, 5 mammals (Guinea pig, ferret, shrew, tenrec, and Tasmanian devil) and 4 oth er evolutionary distinct species have a threonine (Thr) at this position despite high nearby amino acid conservation. This variant has been identified in 26/676 94 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs146278697). -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 19, 2023

- -

Dilated cardiomyopathy 1W

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Dilated cardiomyopathy 1W;C2750459:Hypertrophic cardiomyopathy 15

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 29, 2021

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.087

T;.

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.023

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.86

D;D

M_CAP

Benign

0.0088

MetaRNN

Benign

0.034

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.20

N;N

REVEL

Benign

0.048

Sift

Benign

0.49

T;T

Sift4G

Benign

0.25

T;T

Polyphen

0.13

B;B

Vest4

0.23

MVP

0.043

MPC

0.38

ClinPred

0.022

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.14

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