rs796053216
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS1PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_014191.4(SCN8A):c.4423G>A(p.Gly1475Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.
Frequency
Consequence
NM_014191.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN8A | NM_001330260.2 | c.4423G>A | p.Gly1475Arg | missense_variant | 25/27 | ENST00000627620.5 | |
SCN8A | NM_014191.4 | c.4423G>A | p.Gly1475Arg | missense_variant | 25/27 | ENST00000354534.11 | |
SCN8A | NM_001177984.3 | c.4300G>A | p.Gly1434Arg | missense_variant | 24/26 | ||
SCN8A | NM_001369788.1 | c.4300G>A | p.Gly1434Arg | missense_variant | 24/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN8A | ENST00000354534.11 | c.4423G>A | p.Gly1475Arg | missense_variant | 25/27 | 1 | NM_014191.4 | P4 | |
SCN8A | ENST00000627620.5 | c.4423G>A | p.Gly1475Arg | missense_variant | 25/27 | 5 | NM_001330260.2 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1451118Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 721744
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 19, 2020 | The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29235621, 30776697, 27864847, 29128679, 28923014, 29429461, 30171078, 30615093, 31402610, 32090326, 32040247) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2022 | SCN8A: PM1, PM2, PS4:Moderate, PP2, PP3, PP4, PS3:Supporting - |
Developmental and epileptic encephalopathy, 13 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 29, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | he variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000207119, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.75, 3CNET: 0.972, PP3_P). A missense variant is a common mechanism associated with Developmental and epileptic encephalopathy 13 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). TTherefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1475 of the SCN8A protein (p.Gly1475Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 27864847, 28923014, 30171078). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207119). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN8A protein function. Experimental studies have shown that this missense change affects SCN8A function (PMID: 30615093). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Epileptic encephalopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Neurogenetics Laboratory - MEYER, AOU Meyer | Nov 16, 2016 | - - |
Epilepsy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Nov 06, 2017 | This variant was identified in a mosaic state in a young female patient with epilepsy. - |
Complex neurodevelopmental disorder Other:1
not provided, no classification provided | literature only | Channelopathy-Associated Epilepsy Research Center | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at