chr10-73997822-A-G

Variant names:

• chr10-73997822-A-G
• rs3812624
• ENST00000623461.3:n.79+601A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The ENST00000623461.3(VCL):​n.79+601A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.758 in 152,094 control chromosomes in the GnomAD database, including 44,684 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 0.76 (44684 hom., cov: 33)
• Consequence: VCL ENST00000623461.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.663
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.814 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000623461.3	n.79+601A>G		intron_variant	Intron 2 of 22	1

Frequencies

GnomAD3 genomes AF: 0.758 AC: 115215 AN: 151974 Hom.: 44641 Cov.: 33

Gnomad AFR AF: 0.821

Gnomad AMI AF: 0.667

Gnomad AMR AF: 0.775

Gnomad ASJ AF: 0.817

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.508

Gnomad FIN AF: 0.670

Gnomad MID AF: 0.829

Gnomad NFE AF: 0.779

Gnomad OTH AF: 0.777

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

GnomAD4 genome AF: 0.758 AC: 115308 AN: 152094 Hom.: 44684 Cov.: 33 AF XY: 0.748 AC XY: 55614 AN XY: 74354

African (AFR) AF: 0.821 AC: 34107 AN: 41522

American (AMR) AF: 0.774 AC: 11836 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.817 AC: 2832 AN: 3468

East Asian (EAS) AF: 0.308 AC: 1586 AN: 5144

South Asian (SAS) AF: 0.509 AC: 2452 AN: 4822

European-Finnish (FIN) AF: 0.670 AC: 7090 AN: 10578

Middle Eastern (MID) AF: 0.813 AC: 239 AN: 294

European-Non Finnish (NFE) AF: 0.779 AC: 52924 AN: 67948

Other (OTH) AF: 0.773 AC: 1635 AN: 2116

Alfa AF: 0.774 Hom.: 5700

Bravo AF: 0.766

Asia WGS AF: 0.441 AC: 1535 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	16
DANN	Benign	0.78
PhyloP100		0.66
PromoterAI		-0.00030	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3812624; hg19: chr10-75757580;