10-74000944-A-G

Variant summary

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

The NM_014000.3(VCL):c.168+2569A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.362 in 152,172 control chromosomes in the GnomAD database, including 12,667 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 0.36 (12667 hom., cov: 32)
• Consequence: VCL NM_014000.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.34

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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VCL	NM_014000.3	c.168+2569A>G		intron_variant		ENST00000211998.10
VCL	NM_003373.4	c.168+2569A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCL	ENST00000211998.10	c.168+2569A>G		intron_variant		1	NM_014000.3

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55127 AN: 152054 Hom.: 12669 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.498

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.484

Gnomad EAS AF: 0.0369

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.418

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

GnomAD4 genome AF: 0.362 AC: 55118 AN: 152172 Hom.: 12667 Cov.: 32 AF XY: 0.354 AC XY: 26301 AN XY: 74400

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.442

Gnomad4 ASJ AF: 0.484

Gnomad4 EAS AF: 0.0366

Gnomad4 SAS AF: 0.228

Gnomad4 FIN AF: 0.376

Gnomad4 NFE AF: 0.520

Gnomad4 OTH AF: 0.413

Alfa AF: 0.413 Hom.: 2788

Bravo AF: 0.357

Asia WGS AF: 0.127 AC: 445 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	16
Dann	Benign	0.86

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: rs12357316; hg19: chr10-75760702;