rs2229507

Variant names:

• chr10-74094325-C-T
• rs2229507
• NM_014000.3:c.1407C>T

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.1407C>T​(p.Ala469Ala) 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 1,613,982 control chromosomes in the GnomAD database, including 1,802 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 (869 hom.)
• Consequence: VCL NM_014000.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.785

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=-0.25).
• BP6: Variant 10-74094325-C-T is Benign according to our data. Variant chr10-74094325-C-T is described in ClinVar as [Benign]. Clinvar id is 45579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74094325-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.785 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCL	NM_014000.3	c.1407C>T	p.Ala469Ala	synonymous_variant	Exon 11 of 22	ENST00000211998.10	NP_054706.1
VCL	NM_003373.4	c.1407C>T	p.Ala469Ala	synonymous_variant	Exon 11 of 21		NP_003364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10	c.1407C>T	p.Ala469Ala	synonymous_variant	Exon 11 of 22	1	NM_014000.3	ENSP00000211998.5

Frequencies

GnomAD3 genomes AF: 0.0622 AC: 9447 AN: 151994 Hom.: 933 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0241

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00466

Gnomad OTH AF: 0.0426

GnomAD3 exomes AF: 0.0194 AC: 4868 AN: 251298 Hom.: 395 AF XY: 0.0155 AC XY: 2100 AN XY: 135858

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.0203

Gnomad EAS exome AF: 0.00179

Gnomad SAS exome AF: 0.00287

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00515

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.00990 AC: 14468 AN: 1461870 Hom.: 869 Cov.: 31 AF XY: 0.00905 AC XY: 6580 AN XY: 727236

Gnomad4 AFR exome AF: 0.218

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: 9466 AN: 152112 Hom.: 933 Cov.: 32 AF XY: 0.0600 AC XY: 4462 AN XY: 74386

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: 0.0331 Hom.: 194

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:6

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 04, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 26, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1W Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cardiovascular phenotype Benign:1

Jun 21, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.25
CADD	Benign	7.5
DANN	Benign	0.82
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: rs2229507; hg19: chr10-75854083;