rs767809

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_014000.3(VCL):c.2388G>A(p.Pro796Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 1,612,672 control chromosomes in the GnomAD database, including 236,237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 17014 hom., cov: 31)

Exomes 𝑓: 0.54 ( 219223 hom. )

Consequence

VCL
NM_014000.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:12

Conservation

PhyloP100: -2.66

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:

VCL (HGNC:):

VCL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 10-74105307-G-A is Benign according to our data. Variant chr10-74105307-G-A is described in ClinVar as [Benign]. Clinvar id is 45595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74105307-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.66 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCL	NM_014000.3 linkuse as main transcript	c.2388G>A	p.Pro796Pro	synonymous_variant	16/22	ENST00000211998.10	NP_054706.1	P18206-1V9HWK2B3KXA2
VCL	NM_003373.4 linkuse as main transcript	c.2388G>A	p.Pro796Pro	synonymous_variant	16/21		NP_003364.1	P18206-2A0A024QZN4B3KXA2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10 linkuse as main transcript	c.2388G>A	p.Pro796Pro	synonymous_variant	16/22	1	NM_014000.3	ENSP00000211998.5		P18206-1

Frequencies

GnomAD3 genomes

AF:

0.430

AC:

65358

AN:

151824

Hom.:

17020

Cov.:

show subpopulations

Gnomad AFR

AF:

0.133

Gnomad AMI

AF:

0.415

Gnomad AMR

AF:

0.491

Gnomad ASJ

AF:

0.678

Gnomad EAS

AF:

0.272

Gnomad SAS

AF:

0.403

Gnomad FIN

AF:

0.531

Gnomad MID

AF:

0.554

Gnomad NFE

AF:

0.581

Gnomad OTH

AF:

0.495

GnomAD3 exomes

AF:

0.481

AC:

120803

AN:

251262

Hom.:

31856

AF XY:

0.493

AC XY:

66914

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.124

Gnomad AMR exome

AF:

0.396

Gnomad ASJ exome

AF:

0.684

Gnomad EAS exome

AF:

0.255

Gnomad SAS exome

AF:

0.409

Gnomad FIN exome

AF:

0.545

Gnomad NFE exome

AF:

0.580

Gnomad OTH exome

AF:

0.533

GnomAD4 exome

AF:

0.539

AC:

786625

AN:

1460732

Hom.:

219223

Cov.:

AF XY:

0.538

AC XY:

390910

AN XY:

726660

show subpopulations

Gnomad4 AFR exome

AF:

0.116

Gnomad4 AMR exome

AF:

0.406

Gnomad4 ASJ exome

AF:

0.687

Gnomad4 EAS exome

AF:

0.268

Gnomad4 SAS exome

AF:

0.415

Gnomad4 FIN exome

AF:

0.542

Gnomad4 NFE exome

AF:

0.573

Gnomad4 OTH exome

AF:

0.523

GnomAD4 genome

AF:

0.430

AC:

65338

AN:

151940

Hom.:

17014

Cov.:

AF XY:

0.430

AC XY:

31972

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.132

Gnomad4 AMR

AF:

0.490

Gnomad4 ASJ

AF:

0.678

Gnomad4 EAS

AF:

0.273

Gnomad4 SAS

AF:

0.404

Gnomad4 FIN

AF:

0.531

Gnomad4 NFE

AF:

0.581

Gnomad4 OTH

AF:

0.491

Alfa

AF:

0.527

Hom.:

16473

Bravo

AF:

0.410

Asia WGS

AF:

0.281

AC:

981

AN:

3478

EpiCase

AF:

0.591

EpiControl

AF:

0.596

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 20, 2011	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Dilated cardiomyopathy 1W

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Aganglionic megacolon

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Genetics, Erasmus University Medical Center

May 16, 2019

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Hypertrophic cardiomyopathy 15

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2015

This alteration is classified as 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

BayesDel_noAF

Benign

-0.73

CADD

Benign

3.3

DANN

Benign

0.78

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