rs778236407
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2
The NM_001099404.2(SCN5A):c.5237C>T(p.Ala1746Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A1746T) 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 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.5237C>T | p.Ala1746Val | missense_variant | 28/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.5234C>T | p.Ala1745Val | missense_variant | 28/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.5237C>T | p.Ala1746Val | missense_variant | 28/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.5234C>T | p.Ala1745Val | missense_variant | 28/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152074Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251250Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135870
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461892Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5AN XY: 727248
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152074Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74302
ClinVar
Submissions by phenotype
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 07, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1746 of the SCN5A protein (p.Ala1746Val). This variant is present in population databases (rs778236407, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 463345). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This missense variant replaces alanine with valine at codon 1746 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 15/282592 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at