NM_014000.3:c.499+418C>A

Variant names:

• chr10-74071501-C-A
• rs2131960
• NM_014000.3:c.499+418C>A

Variant summary

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

The NM_014000.3(VCL):​c.499+418C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.664 in 152,044 control chromosomes in the GnomAD database, including 34,485 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 0.66 (34485 hom., cov: 32)
• Consequence: VCL NM_014000.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.359
• Publications: 9 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

LOC124902458 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.762 is higher than 0.05.

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.499+418C>A		intron	N/A	NP_054706.1
	VCL	NM_003373.4		c.499+418C>A		intron	N/A	NP_003364.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCL	ENST00000211998.10	TSL:1 MANE Select	c.499+418C>A		intron	N/A	ENSP00000211998.5
	VCL	ENST00000372755.7	TSL:1	c.499+418C>A		intron	N/A	ENSP00000361841.3
	VCL	ENST00000623461.3	TSL:1	n.457+418C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.665 AC: 100956 AN: 151926 Hom.: 34457 Cov.: 32

Gnomad AFR AF: 0.769

Gnomad AMI AF: 0.533

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.763

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.620

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.648

Gnomad OTH AF: 0.672

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

GnomAD4 genome AF: 0.664 AC: 101031 AN: 152044 Hom.: 34485 Cov.: 32 AF XY: 0.659 AC XY: 48950 AN XY: 74300

African (AFR) AF: 0.769 AC: 31903 AN: 41466

American (AMR) AF: 0.669 AC: 10215 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.763 AC: 2649 AN: 3470

East Asian (EAS) AF: 0.257 AC: 1327 AN: 5172

South Asian (SAS) AF: 0.470 AC: 2267 AN: 4822

European-Finnish (FIN) AF: 0.620 AC: 6546 AN: 10550

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.648 AC: 44036 AN: 67974

Other (OTH) AF: 0.667 AC: 1407 AN: 2110

Alfa AF: 0.635 Hom.: 16926

Bravo AF: 0.669

Asia WGS AF: 0.389 AC: 1357 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.5
DANN	Benign	0.59
PhyloP100		0.36
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: rs2131960; hg19: chr10-75831259;