chr10-74094476-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_014000.3(VCL):c.1543+15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000869 in 1,610,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

VCL
NM_014000.3 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.144

Publications

0 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 10-74094476-G-A is Benign according to our data. Variant chr10-74094476-G-A is described in CliVar as Likely_benign. Clinvar id is 228229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74094476-G-A is described in CliVar as Likely_benign. Clinvar id is 228229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74094476-G-A is described in CliVar as Likely_benign. Clinvar id is 228229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74094476-G-A is described in CliVar as Likely_benign. Clinvar id is 228229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74094476-G-A is described in CliVar as Likely_benign. Clinvar id is 228229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74094476-G-A is described in CliVar as Likely_benign. Clinvar id is 228229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74094476-G-A is described in CliVar as Likely_benign. Clinvar id is 228229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74094476-G-A is described in CliVar as Likely_benign. Clinvar id is 228229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74094476-G-A is described in CliVar as Likely_benign. Clinvar id is 228229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74094476-G-A is described in CliVar as Likely_benign. Clinvar id is 228229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74094476-G-A is described in CliVar as Likely_benign. Clinvar id is 228229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74094476-G-A is described in CliVar as Likely_benign. Clinvar id is 228229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74094476-G-A is described in CliVar as Likely_benign. Clinvar id is 228229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74094476-G-A is described in CliVar as Likely_benign. Clinvar id is 228229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74094476-G-A is described in CliVar as Likely_benign. Clinvar id is 228229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74094476-G-A is described in CliVar as Likely_benign. Clinvar id is 228229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCL	NM_014000.3 link	c.1543+15G>A		intron_variant	Intron 11 of 21	ENST00000211998.10	NP_054706.1	P18206-1V9HWK2B3KXA2
VCL	NM_003373.4 link	c.1543+15G>A		intron_variant	Intron 11 of 20		NP_003364.1	P18206-2A0A024QZN4B3KXA2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10 link	c.1543+15G>A		intron_variant	Intron 11 of 21	1	NM_014000.3	ENSP00000211998.5		P18206-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000370

AC:

AN:

243188

AF XY:

0.0000152

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000239

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.00000823

AC:

AN:

1458174

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

724966

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.000250

AC:

AN:

43962

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25992

East Asian (EAS)

AF:

0.00

AC:

AN:

39636

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53198

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110310

Other (OTH)

AF:

0.00

AC:

AN:

60278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.000131

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 22, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.1543+15G>A in intron 11 of VCL: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence. It has been identified in 3/7402 Latino chromosomes by the Exome Aggregation Conso rtium (ExAC, http://exac.broadinstitute.org; dbSNP rs759560099). -

Dilated cardiomyopathy 1W

Benign:1

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

5.9

(source)

DANN

Benign

0.68

PhyloP100

-0.14

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