rs1874151

Variant names:

• chr10-74107856-C-T
• rs1874151
• NM_014000.3:c.2559+502C>T

Variant summary

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

The NM_014000.3(VCL):​c.2559+502C>T 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 151,794 control chromosomes in the GnomAD database, including 22,244 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 (22244 hom., cov: 31)
• Consequence: VCL NM_014000.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.429
• Publications: 1 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCL	NM_014000.3	c.2559+502C>T		intron_variant	Intron 17 of 21	ENST00000211998.10	NP_054706.1
VCL	NM_003373.4	c.2559+502C>T		intron_variant	Intron 17 of 20		NP_003364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10	c.2559+502C>T		intron_variant	Intron 17 of 21	1	NM_014000.3	ENSP00000211998.5

Frequencies

GnomAD3 genomes AF: 0.530 AC: 80376 AN: 151674 Hom.: 22235 Cov.: 31

Gnomad AFR AF: 0.408

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.534

Gnomad ASJ AF: 0.726

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.425

Gnomad FIN AF: 0.566

Gnomad MID AF: 0.631

Gnomad NFE AF: 0.612

Gnomad OTH AF: 0.582

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

GnomAD4 genome AF: 0.530 AC: 80397 AN: 151794 Hom.: 22244 Cov.: 31 AF XY: 0.527 AC XY: 39077 AN XY: 74148

African (AFR) AF: 0.408 AC: 16863 AN: 41362

American (AMR) AF: 0.533 AC: 8139 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.726 AC: 2519 AN: 3470

East Asian (EAS) AF: 0.295 AC: 1522 AN: 5164

South Asian (SAS) AF: 0.425 AC: 2043 AN: 4802

European-Finnish (FIN) AF: 0.566 AC: 5933 AN: 10488

Middle Eastern (MID) AF: 0.616 AC: 180 AN: 292

European-Non Finnish (NFE) AF: 0.612 AC: 41604 AN: 67940

Other (OTH) AF: 0.576 AC: 1212 AN: 2104

Alfa AF: 0.569 Hom.: 3124

Bravo AF: 0.518

Asia WGS AF: 0.327 AC: 1139 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.8
DANN	Benign	0.47
PhyloP100		0.43
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: rs1874151; hg19: chr10-75867614;