rs777811020

chr10-73998239-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_014000.3(VCL):c.32G>A(p.Ser11Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,460,560 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S11G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: VCL NM_014000.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.06

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 Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, VCL
• BP4: Computational evidence support a benign effect (MetaRNN=0.21065542).
• BS2: High AC in GnomAdExome at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VCL	NM_014000.3	c.32G>A	p.Ser11Asn	missense_variant	1/22	ENST00000211998.10
VCL	NM_003373.4	c.32G>A	p.Ser11Asn	missense_variant	1/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCL	ENST00000211998.10	c.32G>A	p.Ser11Asn	missense_variant	1/22	1	NM_014000.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000405 AC: 10 AN: 246816 Hom.: 0 AF XY: 0.0000224 AC XY: 3 AN XY: 134198

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000549

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460560 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726516

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000227

ExAC AF: 0.0000660 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1W Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 13, 2021

- -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Oct 04, 2017

VCL Ser11Asn c.32G>A, exon 1 (NM_014000.2, hg19 chr10-75757997-G-A) SCICD Classification: We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The rationale for this assessment is: lack of gene-level evidence, lack of case data, frequency of the variant in an ethnicity-matched population. We have seen this variant in a person with HCM. Gene-level evidence: There is limited gene-level evidence linking this gene to HCM. Case data (does not include this patient): none (10/5/2017). Cases in the literature: none reported. Segregation data: none reported. Functional data: none. In silico data (missense variants only): Per the test report, "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")." Conservation data: The serine at codon 11 is conserved across all aligned vertebrates in the UCSC browser. Neighboring amino acids are conserved. Nearby pathogenic variants at this codon or neighboring codons: Another variant affecting the same codon (Ser11Gly, c.31A>G) was listed in ClinVar as a variant of uncertain significance by LMM. No case data provided. Population data: Highest MAF in East Asian population: 0.06%. The variant was reported online in 10 of 120,993 individuals (MAF: 0.004%) in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 10 of 8,548 individuals of East Asian descent (MAF=0.06%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2022

The p.S11N variant (also known as c.32G>A), located in coding exon 1 of the VCL gene, results from a G to A substitution at nucleotide position 32. The serine at codon 11 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.31
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.18	T;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.24
Sift	Benign	0.077	T;D
Sift4G	Benign	0.089	T;T
Polyphen		0.97	D;P
Vest4		0.48
MutPred		0.45		Loss of disorder (P = 0.1381);Loss of disorder (P = 0.1381);
MVP		0.43
MPC		2.4
ClinPred		0.74	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.57

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: rs777811020; hg19: chr10-75757997;