Genetic Variant VCL:c.168+15229C>G (chr10-74013604-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_014000.3(VCL):c.168+15229C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 151,540 control chromosomes in the GnomAD database, including 31,082 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.63 ( 31082 hom., cov: 29)

Consequence

VCL
NM_014000.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.110

Publications

4 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:

ENSG00000225761 (HGNC:):

ENSG00000225761 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCL	NM_014000.3 link	c.168+15229C>G		intron_variant	Intron 1 of 21	ENST00000211998.10	NP_054706.1
VCL	NM_003373.4 link	c.168+15229C>G		intron_variant	Intron 1 of 20		NP_003364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10 link	c.168+15229C>G		intron_variant	Intron 1 of 21	1	NM_014000.3	ENSP00000211998.5

Frequencies

GnomAD3 genomes

AF:

0.631

AC:

95605

AN:

151424

Hom.:

31075

Cov.:

show subpopulations

Gnomad AFR

AF:

0.552

Gnomad AMI

AF:

0.568

Gnomad AMR

AF:

0.700

Gnomad ASJ

AF:

0.739

Gnomad EAS

AF:

0.251

Gnomad SAS

AF:

0.439

Gnomad FIN

AF:

0.617

Gnomad MID

AF:

0.756

Gnomad NFE

AF:

0.702

Gnomad OTH

AF:

0.676

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.631

AC:

95657

AN:

151540

Hom.:

31082

Cov.:

AF XY:

0.625

AC XY:

46249

AN XY:

74038

show subpopulations

African (AFR)

AF:

0.552

AC:

22787

AN:

41266

American (AMR)

AF:

0.699

AC:

10624

AN:

15200

Ashkenazi Jewish (ASJ)

AF:

0.739

AC:

2563

AN:

3468

East Asian (EAS)

AF:

0.251

AC:

1292

AN:

5144

South Asian (SAS)

AF:

0.440

AC:

2108

AN:

4796

European-Finnish (FIN)

AF:

0.617

AC:

6457

AN:

10470

Middle Eastern (MID)

AF:

0.741

AC:

218

AN:

294

European-Non Finnish (NFE)

AF:

0.702

AC:

47679

AN:

67894

Other (OTH)

AF:

0.673

AC:

1412

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1686

3372

5058

6744

8430

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

764

1528

2292

3056

3820

<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:

0.562

Hom.:

1617

Bravo

AF:

0.631

Asia WGS

AF:

0.365

AC:

1271

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

8.6

(source)

DANN

Benign

0.65

PhyloP100

0.11

Mutation Taster

=100/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over