rs1554819693

Positions:

• chr10-74114886-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_014000.3(VCL):​c.3245A>C​(p.Glu1082Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: VCL NM_014000.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VCL. . Gene score misZ 2.7082 (greater than the threshold 3.09). Trascript score misZ 4.2375 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, hypertrophic cardiomyopathy 15, hypertrophic cardiomyopathy, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1W.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31608444).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCL	NM_014000.3	c.3245A>C	p.Glu1082Ala	missense_variant	21/22	ENST00000211998.10	NP_054706.1
VCL	NM_003373.4	c.3041A>C	p.Glu1014Ala	missense_variant	20/21		NP_003364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10	c.3245A>C	p.Glu1082Ala	missense_variant	21/22	1	NM_014000.3	ENSP00000211998
VCL	ENST00000372755.7	c.3041A>C	p.Glu1014Ala	missense_variant	20/21	1		ENSP00000361841	P1
VCL	ENST00000623461.3	n.5844A>C		non_coding_transcript_exon_variant	22/23	1
VCL	ENST00000624354.3	c.*3000A>C		3_prime_UTR_variant, NMD_transcript_variant	20/21	2		ENSP00000485551

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443380 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 716110

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.07e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 1W Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 26, 2017

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 do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with VCL-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with alanine at codon 1082 of the VCL protein (p.Glu1082Ala). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.2	D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.016	D;D
Polyphen		0.88	P;B
Vest4		0.58
MutPred		0.49		Loss of helix (P = 0.0068);.;
MVP		0.45
MPC		2.6
ClinPred		0.96	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.78

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: rs1554819693; hg19: chr10-75874644;