rs16931179

Positions:

• chr10-74111964-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_014000.3(VCL):​c.2801C>T​(p.Ala934Val) variant causes a missense change. The variant allele was found at a frequency of 0.00492 in 1,614,188 control chromosomes in the GnomAD database, including 209 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A934A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0076 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (175 hom.)
• Consequence: VCL NM_014000.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: 4.38

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.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VCL. . Gene score misZ 2.7082 (greater than the threshold 3.09). Trascript score misZ 4.2375 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, hypertrophic cardiomyopathy 15, hypertrophic cardiomyopathy, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1W.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0017710626).
• BP6: Variant 10-74111964-C-T is Benign according to our data. Variant chr10-74111964-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 45599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74111964-C-T is described in Lovd as [Benign]. Variant chr10-74111964-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCL	NM_014000.3	c.2801C>T	p.Ala934Val	missense_variant	19/22	ENST00000211998.10	NP_054706.1
VCL	NM_003373.4	c.2746-2220C>T		intron_variant			NP_003364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10	c.2801C>T	p.Ala934Val	missense_variant	19/22	1	NM_014000.3	ENSP00000211998
VCL	ENST00000372755.7	c.2746-2220C>T		intron_variant		1		ENSP00000361841	P1
VCL	ENST00000623461.3	n.5549-2220C>T		intron_variant, non_coding_transcript_variant		1
VCL	ENST00000624354.3	c.*2556C>T		3_prime_UTR_variant, NMD_transcript_variant	18/21	2		ENSP00000485551

Frequencies

GnomAD3 genomes AF: 0.00751 AC: 1143 AN: 152182 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0162

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0773

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.0337

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.0141 AC: 3546 AN: 251458 Hom.: 93 AF XY: 0.0122 AC XY: 1656 AN XY: 135908

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.0329

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.0796

Gnomad SAS exome AF: 0.00176

Gnomad FIN exome AF: 0.0321

Gnomad NFE exome AF: 0.000888

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.00465 AC: 6795 AN: 1461888 Hom.: 175 Cov.: 30 AF XY: 0.00439 AC XY: 3194 AN XY: 727246

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0313

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.0728

Gnomad4 SAS exome AF: 0.00225

Gnomad4 FIN exome AF: 0.0302

Gnomad4 NFE exome AF: 0.000263

Gnomad4 OTH exome AF: 0.00609

GnomAD4 genome AF: 0.00756 AC: 1151 AN: 152300 Hom.: 34 Cov.: 32 AF XY: 0.00975 AC XY: 726 AN XY: 74484

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.0165

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0771

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.0337

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00421 Hom.: 37

Bravo AF: 0.00780

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0121 AC: 1472

EpiCase AF: 0.000491

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15 Other:1

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 03, 2012	Ala934Val in exon 19 of VCL: This variant is not expected to have clinical signi ficance because it has been identified in 2.5% (54/2160) chromosomes from a broa d, though clinically unspecified population (dbSNP rs16931179; 1000 Genomes proj ect). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Eurofins Ntd Llc (ga)	Nov 17, 2016	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 03, 2020	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Dilated cardiomyopathy 1W Benign:2

Likely 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 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Nov 19, 2015

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 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. -

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

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.48
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.046
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.85	D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.061
Sift	Benign	0.28	T
Sift4G	Benign	0.30	T
Polyphen		0.0010	B
Vest4		0.085
MPC		0.047
ClinPred		0.0084	T
GERP RS		5.3
Varity_R		0.064
gMVP		0.33

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: rs16931179; hg19: chr10-75871722; COSMIC: COSV53009600; COSMIC: COSV53009600;