rs72550247
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_001037.5(SCN1B):c.457G>A(p.Asp153Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D153?) has been classified as Uncertain significance.
Frequency
Consequence
NM_001037.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN1B | NM_001037.5 | c.457G>A | p.Asp153Asn | missense_variant | 4/6 | ENST00000262631.11 | |
SCN1B | NM_001321605.2 | c.358G>A | p.Asp120Asn | missense_variant | 4/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN1B | ENST00000262631.11 | c.457G>A | p.Asp153Asn | missense_variant | 4/6 | 1 | NM_001037.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152220Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251452Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135894
GnomAD4 exome AF: 0.000182 AC: 266AN: 1461850Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 117AN XY: 727228
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74362
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 13, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 04, 2022 | Initially published as a pathogenic variant in an individual with atrial fibrillation, and functional studies show that D153N results in loss of function of the protein (Watanabe et al., 2009); however, as seizures were not reported in the affected individual, the association of D153N with epilepsy, if any, is unknown; Reported previously in two individuals in a large population cohort who had exome sequencing; the authors classified D153N as a variant of unknown significance (Dorschner et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: Garde2020[CaseControl], 27435932, 24055113, 19808477, 21682648, 23838598, 34867379) - |
Atrial fibrillation, familial, 13 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2009 | - - |
Death in early adulthood Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences | Mar 27, 2015 | NM_001037.4:c.457G>A is pathogenic for Death in early adulthood in combination with NM_198056.2:c.1844G>A - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 20, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband with no segregations. In vitro functional study suggests variant results in loss of function; ClinVar: VUS by GeneDx - |
Brugada syndrome 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | The SCN1B gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_001037.5, and corresponds to NM_199037.4:c.*5027G>A in the primary transcript. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 153 of the SCN1B protein (p.Asp153Asn). This variant is present in population databases (rs72550247, gnomAD 0.02%). This missense change has been observed in individual(s) with atrial fibrillation or sudden death (PMID: 19808477, 27435932). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects SCN1B 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. - |
Generalized epilepsy with febrile seizures plus, type 1;C2748541:Brugada syndrome 5;C3809311:Atrial fibrillation, familial, 13;C4479236:Developmental and epileptic encephalopathy, 52 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 22, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 05, 2024 | The p.D153N variant (also known as c.457G>A), located in coding exon 4 of the SCN1B gene, results from a G to A substitution at nucleotide position 457. The aspartic acid at codon 153 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, the clinical significance of this variant for autosomal recessive SCN1B-related early infantile epileptic encephalopathy is unclear; however, due to its observed frequencies in various cohorts, this variant is unlikely to be causative of autosomal dominant SCN1B-related epilepsy and Brugada syndrome. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at