rs777811020
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
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 (★★).
Frequency
Consequence
NM_014000.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000405 AC: 10AN: 246816Hom.: 0 AF XY: 0.0000224 AC XY: 3AN XY: 134198
GnomAD4 exome AF: 0.00000548 AC: 8AN: 1460560Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726516
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1W Uncertain:1
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not provided Uncertain:1
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at