rs374341474
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PP3_StrongBP6BS2
The NM_006514.4(SCN10A):c.2266C>T(p.Arg756Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,618 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R756Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_006514.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN10A | NM_006514.4 | c.2266C>T | p.Arg756Trp | missense_variant | 15/28 | ENST00000449082.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN10A | ENST00000449082.3 | c.2266C>T | p.Arg756Trp | missense_variant | 15/28 | 1 | NM_006514.4 | P4 | |
SCN10A | ENST00000655275.1 | c.2293C>T | p.Arg765Trp | missense_variant | 15/28 | ||||
SCN10A | ENST00000643924.1 | c.2266C>T | p.Arg756Trp | missense_variant | 14/27 | A1 |
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152198Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000559 AC: 14AN: 250520Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135404
GnomAD4 exome AF: 0.0000411 AC: 60AN: 1461420Hom.: 0 Cov.: 31 AF XY: 0.0000440 AC XY: 32AN XY: 727002
GnomAD4 genome AF: 0.000105 AC: 16AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74344
ClinVar
Submissions by phenotype
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 04, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 756 of the SCN10A protein (p.Arg756Trp). This variant is present in population databases (rs374341474, gnomAD 0.03%). This missense change has been observed in individual(s) with a SCN10A-related condition (PMID: 29247119). ClinVar contains an entry for this variant (Variation ID: 532059). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN10A function (PMID: 31195250). 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. - |
Episodic pain syndrome, familial, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 09, 2024 | Variant summary: SCN10A c.2266C>T (p.Arg756Trp) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 250520 control chromosomes. The observed variant frequency is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN10A causing Arrhythmia phenotype (6.3e-06), strongly suggesting that the variant is benign. c.2266C>T has been reported in the literature in at-least one individual affected with sudden unexplained death, however authors classified the variant as VUS (example: Lin_2017). This report does not provide unequivocal conclusions about association of the variant with Arrhythmia. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Gando_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31195250, 29247119). ClinVar contains an entry for this variant (Variation ID: 532059). Based on the evidence outlined above, the variant was classified as likely benign. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 18, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at