rs71579355

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6BP7BS2

The NM_014000.3(VCL):c.1317T>C(p.Ser439Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00536 in 1,614,224 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0043 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0055 ( 25 hom. )

Consequence

VCL
NM_014000.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:14

Conservation

PhyloP100: 0.526

Publications

2 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 -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 10-74090163-T-C is Benign according to our data. Variant chr10-74090163-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45577.

BP7

Synonymous conserved (PhyloP=0.526 with no splicing effect.

BS2

High AC in GnomAd4 at 655 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCL	NM_014000.3	MANE Select	c.1317T>C	p.Ser439Ser	synonymous	Exon 10 of 22	NP_054706.1
	VCL	NM_003373.4		c.1317T>C	p.Ser439Ser	synonymous	Exon 10 of 21	NP_003364.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VCL	ENST00000211998.10	TSL:1 MANE Select	c.1317T>C	p.Ser439Ser	synonymous	Exon 10 of 22	ENSP00000211998.5
VCL	ENST00000372755.7	TSL:1	c.1317T>C	p.Ser439Ser	synonymous	Exon 10 of 21	ENSP00000361841.3
VCL	ENST00000623461.3	TSL:1	n.4120T>C		non_coding_transcript_exon	Exon 12 of 23

Frequencies

GnomAD3 genomes

AF:

0.00430

AC:

655

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00798

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00620

Gnomad OTH

AF:

0.00907

GnomAD2 exomes

AF:

0.00429

AC:

1080

AN:

251482

AF XY:

0.00436

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00515

Gnomad ASJ exome

AF:

0.00546

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.00644

Gnomad OTH exome

AF:

0.00424

GnomAD4 exome

AF:

0.00547

AC:

7998

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00552

AC XY:

4013

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.000896

AC:

AN:

33480

American (AMR)

AF:

0.00557

AC:

249

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00486

AC:

127

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00211

AC:

182

AN:

86258

European-Finnish (FIN)

AF:

0.000618

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00676

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00635

AC:

7065

AN:

1112008

Other (OTH)

AF:

0.00452

AC:

273

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

462

923

1385

1846

2308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

250

500

750

1000

1250

<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:

0.00430

AC:

655

AN:

152348

Hom.:

Cov.:

AF XY:

0.00399

AC XY:

297

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00139

AC:

AN:

41582

American (AMR)

AF:

0.00797

AC:

122

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000376

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00620

AC:

422

AN:

68026

Other (OTH)

AF:

0.00898

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

115

154

192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00523

Hom.:

Bravo

AF:

0.00462

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00682

EpiControl

AF:

0.00788

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (5)

Dilated cardiomyopathy 1W (2)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

8.4

(source)

DANN

Benign

0.75

PhyloP100

0.53

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=97/3

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over