chr12-51751510-A-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP2PP3PP5_Very_Strong
The NM_014191.4(SCN8A):c.2287A>G(p.Ile763Val) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. I763I) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
SCN8A
NM_014191.4 missense
NM_014191.4 missense
Scores
14
3
2
Clinical Significance
Conservation
PhyloP100: 9.32
Genes affected
SCN8A (HGNC:10596): (sodium voltage-gated channel alpha subunit 8) This gene encodes a member of the sodium channel alpha subunit gene family. The encoded protein forms the ion pore region of the voltage-gated sodium channel. This protein is essential for the rapid membrane depolarization that occurs during the formation of the action potential in excitable neurons. Mutations in this gene are associated with cognitive disability, pancerebellar atrophy and ataxia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_014191.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN8A. . Gene score misZ 0.78755 (greater than the threshold 3.09). Trascript score misZ 10.278 (greater than threshold 3.09). GenCC has associacion of gene with myoclonus, familial, 2, infantile convulsions and choreoathetosis, cognitive impairment with or without cerebellar ataxia, undetermined early-onset epileptic encephalopathy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 13, benign familial infantile epilepsy, seizures, benign familial infantile, 5.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.838
PP5
Variant 12-51751510-A-G is Pathogenic according to our data. Variant chr12-51751510-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 194402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN8A | NM_001330260.2 | c.2287A>G | p.Ile763Val | missense_variant | 14/27 | ENST00000627620.5 | |
SCN8A | NM_014191.4 | c.2287A>G | p.Ile763Val | missense_variant | 14/27 | ENST00000354534.11 | |
SCN8A | NM_001177984.3 | c.2287A>G | p.Ile763Val | missense_variant | 14/26 | ||
SCN8A | NM_001369788.1 | c.2287A>G | p.Ile763Val | missense_variant | 14/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN8A | ENST00000354534.11 | c.2287A>G | p.Ile763Val | missense_variant | 14/27 | 1 | NM_014191.4 | P4 | |
SCN8A | ENST00000627620.5 | c.2287A>G | p.Ile763Val | missense_variant | 14/27 | 5 | NM_001330260.2 | A1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 02, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2021 | Not observed at significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29056246, 31487502, 32090326, 27875746) - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 10, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 763 of the SCN8A protein (p.Ile763Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SCN8A-related conditions (PMID: 27875746, 31487502; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 194402). 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 expected to disrupt SCN8A protein function. For these reasons, this variant has been classified as Pathogenic. - |
SCN8A-related disorder Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
D;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;.;H
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
T
PROVEAN
Benign
N;N;N;.;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;.;.
Sift4G
Uncertain
D;D;D;D;D
Polyphen
D;.;.;.;.
Vest4
MutPred
Gain of catalytic residue at I763 (P = 0.0055);Gain of catalytic residue at I763 (P = 0.0055);Gain of catalytic residue at I763 (P = 0.0055);.;Gain of catalytic residue at I763 (P = 0.0055);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at