NM_014000.3:c.2746-777C>G

Variant names:

• chr10-74111132-C-G
• rs16931177
• NM_014000.3:c.2746-777C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014000.3(VCL):​c.2746-777C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.53 in 151,970 control chromosomes in the GnomAD database, including 22,305 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 0.53 (22305 hom., cov: 31)
• Consequence: VCL NM_014000.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.54
• Publications: 4 publications found

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

ACMG classification

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 = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCL	NM_014000.3	c.2746-777C>G		intron_variant	Intron 18 of 21	ENST00000211998.10	NP_054706.1
VCL	NM_003373.4	c.2745+1976C>G		intron_variant	Intron 18 of 20		NP_003364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10	c.2746-777C>G		intron_variant	Intron 18 of 21	1	NM_014000.3	ENSP00000211998.5
VCL	ENST00000372755.7	c.2745+1976C>G		intron_variant	Intron 18 of 20	1		ENSP00000361841.3
VCL	ENST00000623461.3	n.5548+1976C>G		intron_variant	Intron 20 of 22	1
VCL	ENST00000624354.3	n.*2501-777C>G		intron_variant	Intron 17 of 20	2		ENSP00000485551.1

Frequencies

GnomAD3 genomes AF: 0.530 AC: 80522 AN: 151850 Hom.: 22295 Cov.: 31

Gnomad AFR AF: 0.409

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.535

Gnomad ASJ AF: 0.726

Gnomad EAS AF: 0.296

Gnomad SAS AF: 0.425

Gnomad FIN AF: 0.565

Gnomad MID AF: 0.626

Gnomad NFE AF: 0.612

Gnomad OTH AF: 0.581

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

GnomAD4 genome AF: 0.530 AC: 80544 AN: 151970 Hom.: 22305 Cov.: 31 AF XY: 0.527 AC XY: 39153 AN XY: 74266

African (AFR) AF: 0.409 AC: 16929 AN: 41434

American (AMR) AF: 0.534 AC: 8154 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.726 AC: 2521 AN: 3472

East Asian (EAS) AF: 0.296 AC: 1529 AN: 5162

South Asian (SAS) AF: 0.426 AC: 2052 AN: 4818

European-Finnish (FIN) AF: 0.565 AC: 5973 AN: 10572

Middle Eastern (MID) AF: 0.614 AC: 178 AN: 290

European-Non Finnish (NFE) AF: 0.612 AC: 41613 AN: 67944

Other (OTH) AF: 0.575 AC: 1211 AN: 2106

Alfa AF: 0.563 Hom.: 2942

Bravo AF: 0.518

Asia WGS AF: 0.327 AC: 1141 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	0.86
DANN	Benign	0.52
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16931177; hg19: chr10-75870890;