rs199473563
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3
The NM_001099404.2(SCN5A):c.872A>G(p.Asn291Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N291H) 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.872A>G | p.Asn291Ser | missense_variant | 7/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.872A>G | p.Asn291Ser | missense_variant | 7/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.872A>G | p.Asn291Ser | missense_variant | 7/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.872A>G | p.Asn291Ser | missense_variant | 7/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152242Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000803 AC: 2AN: 249126Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135146
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461458Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727028
GnomAD4 genome ? AF: 0.00000656 AC: 1AN: 152360Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74506
ClinVar
Submissions by phenotype
Cardiac arrhythmia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 02, 2023 | This missense variant replaces asparagine with serine at codon 291 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature but has been reported in healthy individuals (PMID: 19841300, 20129283, 25904541). This variant has been identified in 2/249126 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 12, 2023 | This missense variant replaces asparagine with serine at codon 291 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature but has been reported in healthy individuals (PMID: 19841300, 20129283, 25904541). This variant has been identified in 2/249126 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 18, 2023 | The p.N291S variant (also known as c.872A>G), located in coding exon 6 of the SCN5A gene, results from an A to G substitution at nucleotide position 872. The asparagine at codon 291 is replaced by serine, an amino acid with highly similar properties. This variant has been detected in an arrhythmia control cohort (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46). This amino acid position is 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. - |
not provided Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported in the following publications (PMID:19841300;PMID:20129283). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at