rs17121819
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_004588.5(SCN2B):c.82C>T(p.Arg28Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,614,176 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004588.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN2B | ENST00000278947.6 | c.82C>T | p.Arg28Trp | missense_variant | Exon 2 of 4 | 1 | NM_004588.5 | ENSP00000278947.5 | ||
SCN2B | ENST00000658882.1 | n.186C>T | non_coding_transcript_exon_variant | Exon 3 of 5 | ENSP00000499572.1 | |||||
SCN2B | ENST00000665446.1 | n.318C>T | non_coding_transcript_exon_variant | Exon 3 of 4 | ||||||
SCN2B | ENST00000669850.1 | n.324C>T | non_coding_transcript_exon_variant | Exon 2 of 4 |
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000915 AC: 23AN: 251286Hom.: 1 AF XY: 0.0000957 AC XY: 13AN XY: 135826
GnomAD4 exome AF: 0.0000424 AC: 62AN: 1461852Hom.: 1 Cov.: 32 AF XY: 0.0000440 AC XY: 32AN XY: 727224
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152324Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7AN XY: 74486
ClinVar
Submissions by phenotype
Atrial fibrillation, familial, 14 Pathogenic:1Uncertain:2
- -
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 28 of the SCN2B protein (p.Arg28Trp). This variant is present in population databases (rs17121819, gnomAD 0.02%). This missense change has been observed in individual(s) with atrial fibrillation (PMID: 19808477). ClinVar contains an entry for this variant (Variation ID: 60769). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects SCN2B function (PMID: 19808477). 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
Identified in a patient with paroxsymal atrial fibrillation, right precordial saddleback type ST-segment elevation on ECG, and a history of hypertension in published literature (Watanabe et al., 2009); Published functional studies showed reduced peak sodium current amplitude and a positive shift in the voltage dependence of activation, but no effect on the voltage dependence of inactivation or the persistence of the sodium current compared to wild-type SCN2B (Watanabe et al., 2009); In silico analysis supports that this missense variant does not alter protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 26986070, 35385795, 34426522, 19808477) -
Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at