rs1874152

Positions:

• chr10-74076361-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014000.3(VCL):​c.783+1458G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 152,606 control chromosomes in the GnomAD database, including 10,620 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 0.34 (10597 hom., cov: 32)
  • Exomes 𝑓: 0.32 (23 hom.)
• Consequence: VCL NM_014000.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.449

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCL	NM_014000.3	c.783+1458G>A		intron_variant		ENST00000211998.10	NP_054706.1
VCL	NM_003373.4	c.783+1458G>A		intron_variant			NP_003364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10	c.783+1458G>A		intron_variant		1	NM_014000.3	ENSP00000211998

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51535 AN: 152014 Hom.: 10599 Cov.: 32

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.0198

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.467

Gnomad OTH AF: 0.391

GnomAD4 exome AF: 0.316 AC: 150 AN: 474 Hom.: 23 Cov.: 0 AF XY: 0.315 AC XY: 92 AN XY: 292

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 FIN exome AF: 0.319

Gnomad4 NFE exome AF: 0.344

Gnomad4 OTH exome AF: 0.375

GnomAD4 genome AF: 0.339 AC: 51530 AN: 152132 Hom.: 10597 Cov.: 32 AF XY: 0.332 AC XY: 24676 AN XY: 74378

Gnomad4 AFR AF: 0.135

Gnomad4 AMR AF: 0.410

Gnomad4 ASJ AF: 0.482

Gnomad4 EAS AF: 0.0197

Gnomad4 SAS AF: 0.224

Gnomad4 FIN AF: 0.349

Gnomad4 NFE AF: 0.467

Gnomad4 OTH AF: 0.387

Alfa AF: 0.441 Hom.: 15526

Bravo AF: 0.335

Asia WGS AF: 0.134 AC: 466 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.9
DANN	Benign	0.44

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

LitVar

Other links and lift over

dbSNP: rs1874152; hg19: chr10-75836119; COSMIC: COSV53016181;