chr19-35033964-C-T
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The ENST00000415950.5(SCN1B):c.673C>T(p.Arg225Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,552,498 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R225H) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000415950.5 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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN1B | NM_001037.5 | c.448+225C>T | intron_variant | ENST00000262631.11 | |||
SCN1B | NM_199037.5 | c.673C>T | p.Arg225Cys | missense_variant | 3/3 | ||
SCN1B | NM_001321605.2 | c.349+225C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN1B | ENST00000262631.11 | c.448+225C>T | intron_variant | 1 | NM_001037.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152238Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000122 AC: 19AN: 156104Hom.: 0 AF XY: 0.000109 AC XY: 9AN XY: 82454
GnomAD4 exome AF: 0.0000657 AC: 92AN: 1400142Hom.: 1 Cov.: 33 AF XY: 0.0000782 AC XY: 54AN XY: 690716
GnomAD4 genome AF: 0.0000722 AC: 11AN: 152356Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74510
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 10, 2017 | A variant of uncertain significance has been identified in an alternative transcript of the SCN1B gene. The R225C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R225C variant is observed in 2/8002 (0.02%) alleles from individuals of South Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R225C 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 at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Brugada syndrome 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 225 of the SCN1B protein (p.Arg225Cys). This variant is present in population databases (rs369588692, gnomAD 0.02%). This missense change has been observed in individual(s) with sudden infant death syndrome (PMID: 28074886, 29915715). ClinVar contains an entry for this variant (Variation ID: 242250). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The cysteine 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 SCN1B function (PMID: 29915715). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at