rs2131956

Positions:

• chr10-74111977-C-G

Variant summary

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

The NM_014000.3(VCL):​c.2814C>G​(p.Gly938=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.711 in 1,613,952 control chromosomes in the GnomAD database, including 414,207 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (41249 hom., cov: 32)
  • Exomes 𝑓: 0.71 (372958 hom.)
• Consequence: VCL NM_014000.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.39

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 10-74111977-C-G is Benign according to our data. Variant chr10-74111977-C-G is described in ClinVar as [Benign]. Clinvar id is 45600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74111977-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.778 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VCL	NM_014000.3	c.2814C>G	p.Gly938=	synonymous_variant	19/22	ENST00000211998.10
VCL	NM_003373.4	c.2746-2207C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCL	ENST00000211998.10	c.2814C>G	p.Gly938=	synonymous_variant	19/22	1	NM_014000.3
VCL	ENST00000372755.7	c.2746-2207C>G		intron_variant		1		P1
VCL	ENST00000623461.3	n.5549-2207C>G		intron_variant, non_coding_transcript_variant		1
VCL	ENST00000624354.3	c.*2569C>G		3_prime_UTR_variant, NMD_transcript_variant	18/21	2

Frequencies

GnomAD3 genomes AF: 0.730 AC: 110917 AN: 151978 Hom.: 41216 Cov.: 32

Gnomad AFR AF: 0.785

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.704

Gnomad ASJ AF: 0.857

Gnomad EAS AF: 0.394

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.661

Gnomad MID AF: 0.867

Gnomad NFE AF: 0.745

Gnomad OTH AF: 0.774

GnomAD3 exomes AF: 0.669 AC: 168222 AN: 251342 Hom.: 58382 AF XY: 0.670 AC XY: 91045 AN XY: 135858

Gnomad AFR exome AF: 0.780

Gnomad AMR exome AF: 0.582

Gnomad ASJ exome AF: 0.857

Gnomad EAS exome AF: 0.368

Gnomad SAS exome AF: 0.550

Gnomad FIN exome AF: 0.672

Gnomad NFE exome AF: 0.741

Gnomad OTH exome AF: 0.714

GnomAD4 exome AF: 0.709 AC: 1037157 AN: 1461856 Hom.: 372958 Cov.: 85 AF XY: 0.707 AC XY: 513853 AN XY: 727226

Gnomad4 AFR exome AF: 0.784

Gnomad4 AMR exome AF: 0.596

Gnomad4 ASJ exome AF: 0.857

Gnomad4 EAS exome AF: 0.392

Gnomad4 SAS exome AF: 0.554

Gnomad4 FIN exome AF: 0.671

Gnomad4 NFE exome AF: 0.732

Gnomad4 OTH exome AF: 0.718

GnomAD4 genome AF: 0.730 AC: 111003 AN: 152096 Hom.: 41249 Cov.: 32 AF XY: 0.722 AC XY: 53632 AN XY: 74332

Gnomad4 AFR AF: 0.786

Gnomad4 AMR AF: 0.703

Gnomad4 ASJ AF: 0.857

Gnomad4 EAS AF: 0.394

Gnomad4 SAS AF: 0.535

Gnomad4 FIN AF: 0.661

Gnomad4 NFE AF: 0.745

Gnomad4 OTH AF: 0.768

Alfa AF: 0.755 Hom.: 14131

Bravo AF: 0.731

Asia WGS AF: 0.481 AC: 1676 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Dilated cardiomyopathy 1W Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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	-0.51
CADD	Benign	9.1
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2131956; hg19: chr10-75871735; COSMIC: COSV53009612; COSMIC: COSV53009612;