rs747044382
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2
The NM_006514.4(SCN10A):c.3766C>T(p.Arg1256Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R1256Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_006514.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN10A | NM_006514.4 | c.3766C>T | p.Arg1256Trp | missense_variant | 22/28 | ENST00000449082.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN10A | ENST00000449082.3 | c.3766C>T | p.Arg1256Trp | missense_variant | 22/28 | 1 | NM_006514.4 | P4 | |
SCN10A | ENST00000655275.1 | c.3790C>T | p.Arg1264Trp | missense_variant | 22/28 | ||||
SCN10A | ENST00000643924.1 | c.3763C>T | p.Arg1255Trp | missense_variant | 21/27 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251328Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135826
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461620Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727102
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74374
ClinVar
Submissions by phenotype
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 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. 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 expected to disrupt SCN10A protein function. ClinVar contains an entry for this variant (Variation ID: 532125). This missense change has been observed in individual(s) with small fiber neuropathy (PMID: 30554136). This variant is present in population databases (rs747044382, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1256 of the SCN10A protein (p.Arg1256Trp). - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 18, 2023 | The p.R1256W variant (also known as c.3766C>T), located in coding exon 21 of the SCN10A gene, results from a C to T substitution at nucleotide position 3766. The arginine at codon 1256 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was detected in an individual with small fiber neuropathy; however, clinical details were limited (Eijkenboom I et al. J Neurol Neurosurg Psychiatry, 2019 03;90:342-352). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at