rs200645452
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_006514.4(SCN10A):c.5200G>A(p.Glu1734Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000329 in 1,614,028 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_006514.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN10A | ENST00000449082.3 | c.5200G>A | p.Glu1734Lys | missense_variant | Exon 28 of 28 | 1 | NM_006514.4 | ENSP00000390600.2 | ||
SCN10A | ENST00000643924.1 | c.5197G>A | p.Glu1733Lys | missense_variant | Exon 27 of 27 | ENSP00000495595.1 | ||||
SCN10A | ENST00000655275.1 | c.5224G>A | p.Glu1742Lys | missense_variant | Exon 28 of 28 | ENSP00000499510.1 |
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000171 AC: 43AN: 251246Hom.: 0 AF XY: 0.000147 AC XY: 20AN XY: 135756
GnomAD4 exome AF: 0.000346 AC: 506AN: 1461892Hom.: 1 Cov.: 32 AF XY: 0.000331 AC XY: 241AN XY: 727246
GnomAD4 genome AF: 0.000164 AC: 25AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10AN XY: 74300
ClinVar
Submissions by phenotype
Episodic pain syndrome, familial, 2 Uncertain:1
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Brugada syndrome Uncertain:1
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1734 of the SCN10A protein (p.Glu1734Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with small fiber neuropathy (PMID: 30554136). ClinVar contains an entry for this variant (Variation ID: 532083). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SCN10A protein function with a negative predictive value of 80%. 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. -
not provided Uncertain:1
Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 532083; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -
Cardiovascular phenotype Benign:1
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