chr10-74107875-T-C

Position:

• chr10-74107875-T-C

Variant summary

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

The NM_014000.3(VCL):​c.2559+521T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.677 in 151,976 control chromosomes in the GnomAD database, including 35,612 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 0.68 (35612 hom., cov: 31)
• Consequence: VCL NM_014000.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.09

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=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VCL	NM_014000.3	c.2559+521T>C		intron_variant		ENST00000211998.10
VCL	NM_003373.4	c.2559+521T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCL	ENST00000211998.10	c.2559+521T>C		intron_variant		1	NM_014000.3

Frequencies

GnomAD3 genomes AF: 0.677 AC: 102834 AN: 151858 Hom.: 35600 Cov.: 31

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.681

Gnomad ASJ AF: 0.853

Gnomad EAS AF: 0.394

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.745

Gnomad OTH AF: 0.742

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

GnomAD4 genome AF: 0.677 AC: 102886 AN: 151976 Hom.: 35612 Cov.: 31 AF XY: 0.671 AC XY: 49846 AN XY: 74274

Gnomad4 AFR AF: 0.603

Gnomad4 AMR AF: 0.680

Gnomad4 ASJ AF: 0.853

Gnomad4 EAS AF: 0.395

Gnomad4 SAS AF: 0.534

Gnomad4 FIN AF: 0.660

Gnomad4 NFE AF: 0.745

Gnomad4 OTH AF: 0.736

Alfa AF: 0.710 Hom.: 4797

Bravo AF: 0.670

Asia WGS AF: 0.474 AC: 1652 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.3
DANN	Benign	0.51

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: rs1874150; hg19: chr10-75867633;