rs56413529

chr10-74074888-T-Achr10-74074888-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_014000.3(VCL):c.768T>A(p.Asp256Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D256D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VCL NM_014000.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.78

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, VCL

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VCL	NM_014000.3	c.768T>A	p.Asp256Glu	missense_variant	6/22	ENST00000211998.10
VCL	NM_003373.4	c.768T>A	p.Asp256Glu	missense_variant	6/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCL	ENST00000211998.10	c.768T>A	p.Asp256Glu	missense_variant	6/22	1	NM_014000.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1W Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 24, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 536706). This variant has not been reported in the literature in individuals affected with VCL-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 256 of the VCL protein (p.Asp256Glu). -

Dilated cardiomyopathy 1W;C2750459:Hypertrophic cardiomyopathy 15 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.28
Sift	Benign	0.29	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.84	P;D
Vest4		0.60
MutPred		0.62		Gain of catalytic residue at W258 (P = 0.0415);Gain of catalytic residue at W258 (P = 0.0415);
MVP		0.41
MPC		1.1
ClinPred		0.85	D
GERP RS		3.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.25
gMVP		0.37

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: rs56413529; hg19: chr10-75834646;