rs752130196
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP2BP4_ModerateBP6
The NM_001099404.2(SCN5A):c.1372C>T(p.Arg458Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000057 in 1,613,252 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign 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. R458H) has been classified as Uncertain significance.
Frequency
Consequence
NM_001099404.2 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 |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.1372C>T | p.Arg458Cys | missense_variant | 11/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.1372C>T | p.Arg458Cys | missense_variant | 11/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.1372C>T | p.Arg458Cys | missense_variant | 11/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.1372C>T | p.Arg458Cys | missense_variant | 11/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000145 AC: 36AN: 247656Hom.: 1 AF XY: 0.000194 AC XY: 26AN XY: 134340
GnomAD4 exome AF: 0.0000609 AC: 89AN: 1461106Hom.: 1 Cov.: 30 AF XY: 0.0000853 AC XY: 62AN XY: 726746
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74324
ClinVar
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | SCN5A: BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 17, 2019 | This variant is associated with the following publications: (PMID: 25757662, 30122538, 30677491, 31043699) - |
Cardiac arrhythmia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 31, 2023 | This missense variant replaces arginine with cysteine at codon 458 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental functional assays have shown that this variant may affect sodium channel function but clinical relevance of this finding is not clear (PMID: 25757662). This variant has been reported in an individual affected with sudden infant death (PMID: 25757662) and in an individual suspected to be affected with Brugada syndrome (PMID: 36354768). This variant has been identified in 36/247656 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 28, 2023 | This missense variant replaces arginine with cysteine at codon 458 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental functional assays have shown that this variant may affect sodium channel function but clinical relevance of this finding is not clear (PMID: 25757662). This variant has been reported in an individual affected with sudden infant death (PMID: 25757662) and in an individual suspected to be affected with Brugada syndrome (PMID: 36354768). This variant has been identified in 36/247656 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Brugada syndrome 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 08, 2020 | 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