19-35033883-A-G
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_199037.5(SCN1B):c.592A>G(p.Ser198Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 1,600,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_199037.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN1B | NM_001037.5 | c.448+144A>G | intron_variant | Intron 3 of 5 | ENST00000262631.11 | NP_001028.1 | ||
SCN1B | NM_199037.5 | c.592A>G | p.Ser198Gly | missense_variant | Exon 3 of 3 | NP_950238.1 | ||
SCN1B | NM_001321605.2 | c.349+144A>G | intron_variant | Intron 3 of 5 | NP_001308534.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152058Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000495 AC: 11AN: 222284Hom.: 0 AF XY: 0.0000497 AC XY: 6AN XY: 120676
GnomAD4 exome AF: 0.0000138 AC: 20AN: 1447984Hom.: 0 Cov.: 33 AF XY: 0.0000139 AC XY: 10AN XY: 718852
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152058Hom.: 0 Cov.: 31 AF XY: 0.0000808 AC XY: 6AN XY: 74264
ClinVar
Submissions by phenotype
Brugada syndrome 5 Uncertain:1
This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 198 of the SCN1B protein (p.Ser198Gly). This variant is present in population databases (rs763402433, gnomAD 0.03%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 24981977). ClinVar contains an entry for this variant (Variation ID: 190864). 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. -
not provided Uncertain:1
p.Ser198Gly (AGC>GGC): c.592 A>G in exon 3 of the SCN1B gene (NM_199037.2). The S198G variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The S198G variant was not observed in approximately 3600 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. One missense mutation in a nearby residue (Q204R) has been reported in association with Brugada syndrome. The S198G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs in an alternate transcript of the SCN1B protein at a position that is not conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. Brugada syndrome is primarily an autosomal dominant disease characterized by ST segment elevation on ECG in the absence of structural heart disease, associated with increased risk for syncope, ventricular tachyarrhythmia and sudden cardiac death. Brugada syndrome is most frequently caused by mutations in the genes encoding cardiac ion channel proteins, which regulate sodium and calcium movement in and out of cardiac cells (Fowler S et al., 2008; Hedley P et al., 2009). Although rare, mutations in the SCN1B gene have been reported in association with Brugada syndrome (Brugada R et al., 2012). The variant is found in BRUGADA panel(s). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at