rs768691853
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2
The NM_000335.5(SCN5A):c.2962C>T(p.Arg988Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,609,516 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 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.2962C>T | p.Arg988Trp | missense_variant | Exon 17 of 28 | ENST00000413689.6 | NP_001092874.1 | |
SCN5A | NM_000335.5 | c.2962C>T | p.Arg988Trp | missense_variant | Exon 17 of 28 | ENST00000423572.7 | NP_000326.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.2962C>T | p.Arg988Trp | missense_variant | Exon 17 of 28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
SCN5A | ENST00000423572.7 | c.2962C>T | p.Arg988Trp | missense_variant | Exon 17 of 28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes AF: 0.0000397 AC: 6AN: 151304Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000210 AC: 5AN: 238498Hom.: 0 AF XY: 0.00000768 AC XY: 1AN XY: 130238
GnomAD4 exome AF: 0.0000158 AC: 23AN: 1458212Hom.: 0 Cov.: 36 AF XY: 0.0000110 AC XY: 8AN XY: 725138
GnomAD4 genome AF: 0.0000397 AC: 6AN: 151304Hom.: 0 Cov.: 32 AF XY: 0.0000406 AC XY: 3AN XY: 73820
ClinVar
Submissions by phenotype
not provided Uncertain:4
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This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 988 of the SCN5A protein (p.Arg988Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Brugada syndrome and/or dilated cardiomyopathy (PMID: 23321620, 30165862). ClinVar contains an entry for this variant (Variation ID: 201486). 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 disruptive. 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 Brugada syndrome, but it is unknown whether this individual was screened for variants in other genes associated with Brugada syndrome (Sommariva et al., 2013); Identified in a patient with dilated cardiomyopathy who also harbored a variant in the RBM20 gene (Lu et al., 2018); 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: 30662450, 23321620, 30165862) -
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Cardiac arrhythmia Uncertain:2
This missense variant replaces arginine with tryptophan at codon 988 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two unrelated individuals affected with Brugada syndrome (PMID: 23321620, 32268277) and in an individual with dilated cardiomyopathy (PMID: 30165862). This variant has been identified in 5/238498 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. -
This missense variant replaces arginine with tryptophan at codon 988 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two unrelated individuals affected with Brugada syndrome (PMID: 23321620, 32268277) and in an individual with dilated cardiomyopathy (PMID: 30165862). This variant has been identified in 5/238498 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. -
SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at