12-51769230-C-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2
The NM_014191.4(SCN8A):c.3267C>A(p.Asn1089Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,698 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1089S) has been classified as Likely benign.
Frequency
Consequence
NM_014191.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN8A | NM_001330260.2 | c.3267C>A | p.Asn1089Lys | missense_variant | 17/27 | ENST00000627620.5 | |
SCN8A | NM_014191.4 | c.3267C>A | p.Asn1089Lys | missense_variant | 17/27 | ENST00000354534.11 | |
SCN8A | NM_001177984.3 | c.3267C>A | p.Asn1089Lys | missense_variant | 17/26 | ||
SCN8A | NM_001369788.1 | c.3267C>A | p.Asn1089Lys | missense_variant | 17/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN8A | ENST00000354534.11 | c.3267C>A | p.Asn1089Lys | missense_variant | 17/27 | 1 | NM_014191.4 | P4 | |
SCN8A | ENST00000627620.5 | c.3267C>A | p.Asn1089Lys | missense_variant | 17/27 | 5 | NM_001330260.2 | A1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250118Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135318
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461698Hom.: 1 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727130
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 13 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 03, 2017 | - - |
Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2022 | 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. 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) performed at Invitae indicates that this missense variant is not expected to disrupt SCN8A protein function. ClinVar contains an entry for this variant (Variation ID: 522699). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. This variant is present in population databases (rs761386688, gnomAD 0.003%). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1089 of the SCN8A protein (p.Asn1089Lys). - |
See cases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Apr 18, 2023 | ACMG categories: PM2 - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at