rs2228373

Positions:

• chr10-74094424-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_014000.3(VCL):​c.1506G>A​(p.Arg502Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 1,614,038 control chromosomes in the GnomAD database, including 1,801 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (933 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (868 hom.)
• Consequence: VCL NM_014000.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.575

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 10-74094424-G-A is Benign according to our data. Variant chr10-74094424-G-A is described in ClinVar as [Benign]. Clinvar id is 45580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74094424-G-A is described in Lovd as [Benign]. Variant chr10-74094424-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.575 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCL	NM_014000.3	c.1506G>A	p.Arg502Arg	synonymous_variant	11/22	ENST00000211998.10	NP_054706.1
VCL	NM_003373.4	c.1506G>A	p.Arg502Arg	synonymous_variant	11/21		NP_003364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10	c.1506G>A	p.Arg502Arg	synonymous_variant	11/22	1	NM_014000.3	ENSP00000211998.5

Frequencies

GnomAD3 genomes AF: 0.0621 AC: 9451 AN: 152114 Hom.: 933 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0242

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00466

Gnomad OTH AF: 0.0425

GnomAD3 exomes AF: 0.0193 AC: 4848 AN: 251062 Hom.: 390 AF XY: 0.0154 AC XY: 2091 AN XY: 135758

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.0203

Gnomad EAS exome AF: 0.00180

Gnomad SAS exome AF: 0.00288

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00514

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.00989 AC: 14452 AN: 1461806 Hom.: 868 Cov.: 31 AF XY: 0.00904 AC XY: 6572 AN XY: 727194

Gnomad4 AFR exome AF: 0.217

Gnomad4 AMR exome AF: 0.0131

Gnomad4 ASJ exome AF: 0.0199

Gnomad4 EAS exome AF: 0.000957

Gnomad4 SAS exome AF: 0.00317

Gnomad4 FIN exome AF: 0.000524

Gnomad4 NFE exome AF: 0.00405

Gnomad4 OTH exome AF: 0.0184

GnomAD4 genome AF: 0.0622 AC: 9470 AN: 152232 Hom.: 933 Cov.: 32 AF XY: 0.0600 AC XY: 4462 AN XY: 74424

Gnomad4 AFR AF: 0.207

Gnomad4 AMR AF: 0.0241

Gnomad4 ASJ AF: 0.0219

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00466

Gnomad4 OTH AF: 0.0421

Alfa AF: 0.0299 Hom.: 201

Bravo AF: 0.0713

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.00627

EpiControl AF: 0.00528

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2013	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	Dec 04, 2008	- -
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	Clinical Genetics, Academic 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. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 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	-0.33
CADD	Benign	7.7
DANN	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs2228373; hg19: chr10-75854182; COSMIC: COSV53016225;