rs148663098
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_006514.4(SCN10A):c.410C>T(p.Thr137Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,610,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T137T) has been classified as Likely benign.
Frequency
Consequence
NM_006514.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN10A | NM_006514.4 | c.410C>T | p.Thr137Met | missense_variant | 4/28 | ENST00000449082.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN10A | ENST00000449082.3 | c.410C>T | p.Thr137Met | missense_variant | 4/28 | 1 | NM_006514.4 | P4 | |
SCN10A | ENST00000655275.1 | c.410C>T | p.Thr137Met | missense_variant | 4/28 | ||||
SCN10A | ENST00000643924.1 | c.410C>T | p.Thr137Met | missense_variant | 3/27 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152108Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250726Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135514
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1458590Hom.: 0 Cov.: 28 AF XY: 0.00000964 AC XY: 7AN XY: 725836
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152108Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74292
ClinVar
Submissions by phenotype
Brugada syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | - - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 19, 2022 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 137 of the SCN10A protein (p.Thr137Met). This variant is present in population databases (rs148663098, gnomAD 0.003%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 24998131). ClinVar contains an entry for this variant (Variation ID: 463256). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 26, 2020 | Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 463256; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); At the protein level, in silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24998131, 28407228, 30821013) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 23, 2023 | The p.T137M variant (also known as c.410C>T), located in coding exon 3 of the SCN10A gene, results from a C to T substitution at nucleotide position 410. The threonine at codon 137 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in a Brugada syndrome cohort, as well as an autism spectrum disorder whole exome sequencing cohort (Hu D et al. J Am Coll Cardiol, 2014 Jul;64:66-79; Abou Ziki MD et al. Clin Genet, 2018 04;93:741-751; Patowary A et al. Transl Psychiatry, 2019 01;9:4). This amino acid position is not well conserved in available vertebrate species, and methionine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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