chr10-74105307-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_014000.3(VCL):c.2388G>A(p.Pro796Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 1,612,672 control chromosomes in the GnomAD database, including 236,237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 17014 hom., cov: 31)

Exomes 𝑓: 0.54 ( 219223 hom. )

Consequence

VCL
NM_014000.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:13

Conservation

PhyloP100: -2.66

Publications

25 publications found

Variant links:

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

VCL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 10-74105307-G-A is Benign according to our data. Variant chr10-74105307-G-A is described in ClinVar as Benign. ClinVar VariationId is 45595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.66 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCL	NM_014000.3 link	c.2388G>A	p.Pro796Pro	synonymous_variant	Exon 16 of 22	ENST00000211998.10	NP_054706.1
VCL	NM_003373.4 link	c.2388G>A	p.Pro796Pro	synonymous_variant	Exon 16 of 21		NP_003364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10 link	c.2388G>A	p.Pro796Pro	synonymous_variant	Exon 16 of 22	1	NM_014000.3	ENSP00000211998.5

Frequencies

GnomAD3 genomes

AF:

0.430

AC:

65358

AN:

151824

Hom.:

17020

Cov.:

show subpopulations

Gnomad AFR

AF:

0.133

Gnomad AMI

AF:

0.415

Gnomad AMR

AF:

0.491

Gnomad ASJ

AF:

0.678

Gnomad EAS

AF:

0.272

Gnomad SAS

AF:

0.403

Gnomad FIN

AF:

0.531

Gnomad MID

AF:

0.554

Gnomad NFE

AF:

0.581

Gnomad OTH

AF:

0.495

GnomAD2 exomes

AF:

0.481

AC:

120803

AN:

251262

AF XY:

0.493

show subpopulations

Gnomad AFR exome

AF:

0.124

Gnomad AMR exome

AF:

0.396

Gnomad ASJ exome

AF:

0.684

Gnomad EAS exome

AF:

0.255

Gnomad FIN exome

AF:

0.545

Gnomad NFE exome

AF:

0.580

Gnomad OTH exome

AF:

0.533

GnomAD4 exome

AF:

0.539

AC:

786625

AN:

1460732

Hom.:

219223

Cov.:

AF XY:

0.538

AC XY:

390910

AN XY:

726660

show subpopulations

African (AFR)

AF:

0.116

AC:

3869

AN:

33436

American (AMR)

AF:

0.406

AC:

18153

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.687

AC:

17947

AN:

26134

East Asian (EAS)

AF:

0.268

AC:

10645

AN:

39700

South Asian (SAS)

AF:

0.415

AC:

35797

AN:

86206

European-Finnish (FIN)

AF:

0.542

AC:

28978

AN:

53420

Middle Eastern (MID)

AF:

0.609

AC:

2952

AN:

4848

European-Non Finnish (NFE)

AF:

0.573

AC:

636735

AN:

1111972

Other (OTH)

AF:

0.523

AC:

31549

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

22659

45317

67976

90634

113293

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17272

34544

51816

69088

86360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.430

AC:

65338

AN:

151940

Hom.:

17014

Cov.:

AF XY:

0.430

AC XY:

31972

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.132

AC:

5488

AN:

41424

American (AMR)

AF:

0.490

AC:

7487

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.678

AC:

2353

AN:

3470

East Asian (EAS)

AF:

0.273

AC:

1405

AN:

5154

South Asian (SAS)

AF:

0.404

AC:

1946

AN:

4818

European-Finnish (FIN)

AF:

0.531

AC:

5596

AN:

10544

Middle Eastern (MID)

AF:

0.537

AC:

158

AN:

294

European-Non Finnish (NFE)

AF:

0.581

AC:

39493

AN:

67944

Other (OTH)

AF:

0.491

AC:

1036

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1647

3294

4940

6587

8234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

586

1172

1758

2344

2930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.525

Hom.:

21137

Bravo

AF:

0.410

Asia WGS

AF:

0.281

AC:

981

AN:

3478

EpiCase

AF:

0.591

EpiControl

AF:

0.596

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

PreventionGenetics, part of Exact Sciences

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

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 01, 2012

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.

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 20, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dilated cardiomyopathy 1W

Benign:2

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.

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aganglionic megacolon

Uncertain:1

May 16, 2019

Clinical Genetics, Erasmus University Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Hypertrophic cardiomyopathy 15

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Mar 11, 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

-0.73

CADD

Benign

3.3

(source)

DANN

Benign

0.78

PhyloP100

-2.7

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over