rs201106879
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_006514.4(SCN10A):c.3070G>A(p.Val1024Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000566 in 1,590,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_006514.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN10A | NM_006514.4 | c.3070G>A | p.Val1024Met | missense_variant | 17/28 | ENST00000449082.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN10A | ENST00000449082.3 | c.3070G>A | p.Val1024Met | missense_variant | 17/28 | 1 | NM_006514.4 | P4 | |
SCN10A | ENST00000655275.1 | c.3097G>A | p.Val1033Met | missense_variant | 17/28 | ||||
SCN10A | ENST00000643924.1 | c.3070G>A | p.Val1024Met | missense_variant | 16/27 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152228Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000206 AC: 5AN: 243042Hom.: 0 AF XY: 0.0000230 AC XY: 3AN XY: 130664
GnomAD4 exome AF: 0.00000348 AC: 5AN: 1437718Hom.: 0 Cov.: 30 AF XY: 0.00000282 AC XY: 2AN XY: 710344
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152346Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2AN XY: 74496
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 20, 2021 | Reported in an individual with early onset atrial fibrillation and a structurally normal heart; this individual also harbored a frameshift variant in the TTN gene that was reported as likely pathogenic (Goodyer et al., 2019); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID#463246; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31638414, 23986244, 24998131) - |
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Apr 25, 2017 | Found in a 16 year-old male with lone atrial fibrillation and a family history of heart failure and arrhythmias. Testing was done at Invitae. p.Val1024Met (c.3070G>A) in exon 16 of the SCN10A gene (NM_006514.3) Chromosome position: 3:38768114 C / T The SCN10A gene currently has no well-established disease association; however, there is preliminary evidence supporting a correlation with autosomal dominant small fiber neuropathy (SFNP) (PMID: 23986244) and Brugada syndrome (BrS) (PMID: 24998131). Based on the information reviewed below, including that this is a conservative amino acid change at a residue that is poorly conserved across species, and where Methionine is accepted as the default in some species, we classify it as a Variant of Uncertain Significance, Probably Benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. This variant has not previously been reported in the literature in association with disease. It had not been reported to ClinVar as of 4/25/2017. This is a conservative amino acid change, resulting in the replacement of a nonpolar Valine with a nonpolar Methionine. Valine at this location is poorly conserved across ~80 vertebrate species for which we have data. In fact, Methionine is the default amino acid in at least two mammalian species, suggesting that this missense change does not adversely affect protein function. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". These predictions have not been confirmed by published functional studies. There is no Likely Pathogenic or Pathogenic missense variant currently listed in ClinVar at a nearby residue (+/- 10). This variant was reported in 4 individuals in the gnomAD database, which includes ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 2 individuals with African ancestry (for the highest allele frequency: 0.013%), and 2 individuals with Latino ancestry. Our patient’s ancestry is Latino. 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. The curators made an effort to exclude individuals with severe pediatric diseases. - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2022 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1024 of the SCN10A protein (p.Val1024Met). This variant is present in population databases (rs201106879, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SCN10A-related conditions. ClinVar contains an entry for this variant (Variation ID: 463246). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SCN10A protein function. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 15, 2022 | The p.V1024M variant (also known as c.3070G>A), located in coding exon 16 of the SCN10A gene, results from a G to A substitution at nucleotide position 3070. The valine at codon 1024 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. 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