rs137877092

chr10-74095783-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_014000.3(VCL):c.1671C>T(p.Asp557=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,614,146 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (56 hom.)
• Consequence: VCL NM_014000.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.523

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 10-74095783-C-T is Benign according to our data. Variant chr10-74095783-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 45587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74095783-C-T is described in Lovd as [Benign]. Variant chr10-74095783-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.523 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00264 (402/152276) while in subpopulation SAS AF= 0.0145 (70/4832). AF 95% confidence interval is 0.0118. There are 1 homozygotes in gnomad4. There are 253 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 403 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VCL	NM_014000.3	c.1671C>T	p.Asp557=	synonymous_variant	12/22	ENST00000211998.10
VCL	NM_003373.4	c.1671C>T	p.Asp557=	synonymous_variant	12/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCL	ENST00000211998.10	c.1671C>T	p.Asp557=	synonymous_variant	12/22	1	NM_014000.3

Frequencies

GnomAD3 genomes AF: 0.00265 AC: 403 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00493 AC: 1240 AN: 251426 Hom.: 18 AF XY: 0.00585 AC XY: 795 AN XY: 135900

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0176

Gnomad FIN exome AF: 0.0157

Gnomad NFE exome AF: 0.00222

Gnomad OTH exome AF: 0.00472

GnomAD4 exome AF: 0.00295 AC: 4319 AN: 1461870 Hom.: 56 Cov.: 31 AF XY: 0.00346 AC XY: 2519 AN XY: 727236

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00448

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0181

Gnomad4 FIN exome AF: 0.0164

Gnomad4 NFE exome AF: 0.00129

Gnomad4 OTH exome AF: 0.00382

GnomAD4 genome AF: 0.00264 AC: 402 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.00340 AC XY: 253 AN XY: 74456

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.0150

Gnomad4 NFE AF: 0.00172

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00229 Hom.: 0

Bravo AF: 0.00118

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.00311

EpiControl AF: 0.00290

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 30, 2017	p.Asp557Asp in exon 12 of VCL: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and has been identifie d in 1.6% (105/6612) of European chromosomes by the Exome Aggregation Consortiu m (ExAC, http://exac.broadinstitute.org; dbSNP rs137877092). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2014	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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 04, 2019	Variant summary: The variant, VCL c.1671C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0049 in 277182 control chromosomes in the gnomAD database. The highest allele frequencies were detected within the South Asian (0.018) and the Finnish subpopulation (0.016), including 12 and 7 homozygotes, respectively. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 720 fold of the estimated maximal expected allele frequency for a pathogenic variant in VCL causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism. The variant, c.1671C>T has been reported in the literature in individuals affected with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) (Pugh 2014, Bottillo 2016), however, without evidence for pathogenicity. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (four classifying it as benign and one as a VUS). Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Dilated cardiomyopathy 1W Benign:2

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Mar 07, 2016

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 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	-0.39
Cadd	Benign	8.6
Dann	Benign	0.77
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: rs137877092; hg19: chr10-75855541;