10-74074888-T-C

Variant names:

• chr10-74074888-T-C
• rs56413529
• NM_014000.3:c.768T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014000.3(VCL):​c.768T>C​(p.Asp256Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,614,064 control chromosomes in the GnomAD database, including 1,846 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (1031 hom., cov: 32)
  • Exomes 𝑓: 0.0066 (815 hom.)
• Consequence: VCL NM_014000.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.78
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy 1W

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy 15

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 10-74074888-T-C is Benign according to our data. Variant chr10-74074888-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.78 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014000.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCL	NM_014000.3	MANE Select	c.768T>C	p.Asp256Asp	synonymous	Exon 6 of 22	NP_054706.1
	VCL	NM_003373.4		c.768T>C	p.Asp256Asp	synonymous	Exon 6 of 21	NP_003364.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCL	ENST00000211998.10	TSL:1 MANE Select	c.768T>C	p.Asp256Asp	synonymous	Exon 6 of 22	ENSP00000211998.5
	VCL	ENST00000372755.7	TSL:1	c.768T>C	p.Asp256Asp	synonymous	Exon 6 of 21	ENSP00000361841.3
	VCL	ENST00000623461.3	TSL:1	n.726T>C		non_coding_transcript_exon	Exon 8 of 23

Frequencies

GnomAD3 genomes AF: 0.0627 AC: 9537 AN: 152118 Hom.: 1030 Cov.: 32

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0221

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000999

Gnomad OTH AF: 0.0416

GnomAD2 exomes AF: 0.0170 AC: 4264 AN: 251330 AF XY: 0.0128

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.0100

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000897

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.00660 AC: 9644 AN: 1461828 Hom.: 815 Cov.: 31 AF XY: 0.00583 AC XY: 4241 AN XY: 727218

African (AFR) AF: 0.217 AC: 7256 AN: 33470

American (AMR) AF: 0.0108 AC: 482 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 407 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39688

South Asian (SAS) AF: 0.000603 AC: 52 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.0135 AC: 78 AN: 5766

European-Non Finnish (NFE) AF: 0.000416 AC: 463 AN: 1111986

Other (OTH) AF: 0.0150 AC: 904 AN: 60390

GnomAD4 genome AF: 0.0628 AC: 9556 AN: 152236 Hom.: 1031 Cov.: 32 AF XY: 0.0600 AC XY: 4467 AN XY: 74446

African (AFR) AF: 0.216 AC: 8970 AN: 41486

American (AMR) AF: 0.0221 AC: 338 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.000999 AC: 68 AN: 68034

Other (OTH) AF: 0.0421 AC: 89 AN: 2112

Alfa AF: 0.0303 Hom.: 224

Bravo AF: 0.0707

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.000873

EpiControl AF: 0.00119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 17, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 05, 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.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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 12, 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:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiomyopathy Benign:1

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

Dilated cardiomyopathy 1W;C2750459:Hypertrophic cardiomyopathy 15 Benign:1

May 02, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Jun 25, 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.1
DANN	Benign	0.62
PhyloP100		1.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs56413529; hg19: chr10-75834646;