3-38608190-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_000335.5(SCN5A):c.959C>A(p.Thr320Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,582 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000335.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.959C>A | p.Thr320Asn | missense_variant | Exon 8 of 28 | ENST00000413689.6 | NP_001092874.1 | |
SCN5A | NM_000335.5 | c.959C>A | p.Thr320Asn | missense_variant | Exon 8 of 28 | ENST00000423572.7 | NP_000326.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.959C>A | p.Thr320Asn | missense_variant | Exon 8 of 28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
SCN5A | ENST00000423572.7 | c.959C>A | p.Thr320Asn | missense_variant | Exon 8 of 28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249254Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135224
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1459582Hom.: 0 Cov.: 28 AF XY: 0.00000413 AC XY: 3AN XY: 726260
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:2
This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 320 of the SCN5A protein (p.Thr320Asn). This variant is present in population databases (rs199473091, gnomAD 0.03%). This missense change has been observed in individual(s) with Brugada syndrome or long-QT syndrome (PMID: 19841300, 25904541). ClinVar contains an entry for this variant (Variation ID: 68061). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -
Identified in a patient with suspected Brugada syndrome in the published literature (Kapplinger et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20129283, 30662450) -
Brugada syndrome Other:1
This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at