chr3-38752241-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_006514.4(SCN10A):c.1733C>A(p.Ala578Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,392,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. A578V) 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.1733C>A | p.Ala578Asp | missense_variant | 12/28 | ENST00000449082.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN10A | ENST00000449082.3 | c.1733C>A | p.Ala578Asp | missense_variant | 12/28 | 1 | NM_006514.4 | P4 | |
SCN10A | ENST00000655275.1 | c.1760C>A | p.Ala587Asp | missense_variant | 12/28 | ||||
SCN10A | ENST00000643924.1 | c.1733C>A | p.Ala578Asp | missense_variant | 11/27 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000508 AC: 1AN: 196922Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 105680
GnomAD4 exome AF: 0.00000144 AC: 2AN: 1392066Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1AN XY: 687606
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 15, 2022 | 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. This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 578 of the SCN10A protein (p.Ala578Asp). This variant is present in population databases (rs535115766, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with SCN10A-related conditions. 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 | Dec 21, 2020 | The p.A578D variant (also known as c.1733C>A), located in coding exon 11 of the SCN10A gene, results from a C to A substitution at nucleotide position 1733. The alanine at codon 578 is replaced by aspartic acid, an amino acid with dissimilar properties. This amino acid position is not well 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