rs10762573

Variant names:

• chr10-74038390-A-C
• rs10762573
• NM_014000.3:c.169-4693A>C

Variant summary

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

The NM_014000.3(VCL):​c.169-4693A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.666 in 152,048 control chromosomes in the GnomAD database, including 34,550 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 0.67 (34550 hom., cov: 31)
• Consequence: VCL NM_014000.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.44
• Publications: 10 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.753 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCL	NM_014000.3	MANE Select	c.169-4693A>C		intron	N/A	NP_054706.1
	VCL	NM_003373.4		c.169-4693A>C		intron	N/A	NP_003364.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCL	ENST00000211998.10	TSL:1 MANE Select	c.169-4693A>C		intron	N/A	ENSP00000211998.5
	VCL	ENST00000372755.7	TSL:1	c.169-4693A>C		intron	N/A	ENSP00000361841.3
	VCL	ENST00000623461.3	TSL:1	n.127-4693A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.666 AC: 101251 AN: 151930 Hom.: 34519 Cov.: 31

Gnomad AFR AF: 0.760

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.688

Gnomad ASJ AF: 0.763

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.622

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.651

Gnomad OTH AF: 0.678

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

GnomAD4 genome AF: 0.666 AC: 101331 AN: 152048 Hom.: 34550 Cov.: 31 AF XY: 0.661 AC XY: 49144 AN XY: 74312

African (AFR) AF: 0.760 AC: 31536 AN: 41496

American (AMR) AF: 0.688 AC: 10507 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.763 AC: 2650 AN: 3472

East Asian (EAS) AF: 0.297 AC: 1534 AN: 5160

South Asian (SAS) AF: 0.463 AC: 2236 AN: 4828

European-Finnish (FIN) AF: 0.622 AC: 6560 AN: 10542

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.651 AC: 44216 AN: 67956

Other (OTH) AF: 0.675 AC: 1425 AN: 2112

Alfa AF: 0.656 Hom.: 52326

Bravo AF: 0.671

Asia WGS AF: 0.396 AC: 1380 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.78
DANN	Benign	0.63
PhyloP100		-1.4
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: rs10762573; hg19: chr10-75798148;