chr12-51662821-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_014191.4(SCN8A):c.4G>A(p.Ala2Thr) 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 Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Consequence
SCN8A
NM_014191.4 missense
NM_014191.4 missense
Scores
9
3
1
Clinical Significance
Conservation
PhyloP100: 10.0
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, SCN8A
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.862
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN8A | NM_001330260.2 | c.4G>A | p.Ala2Thr | missense_variant | 2/27 | ENST00000627620.5 | |
SCN8A | NM_014191.4 | c.4G>A | p.Ala2Thr | missense_variant | 2/27 | ENST00000354534.11 | |
SCN8A | NM_001177984.3 | c.4G>A | p.Ala2Thr | missense_variant | 2/26 | ||
SCN8A | NM_001369788.1 | c.4G>A | p.Ala2Thr | missense_variant | 2/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN8A | ENST00000354534.11 | c.4G>A | p.Ala2Thr | missense_variant | 2/27 | 1 | NM_014191.4 | P4 | |
SCN8A | ENST00000627620.5 | c.4G>A | p.Ala2Thr | missense_variant | 2/27 | 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: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 28, 2021 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SCN8A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 2 of the SCN8A protein (p.Ala2Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
T
Polyphen
1.0
.;D;.;.;.;.
Vest4
0.49, 0.47, 0.46, 0.57, 0.49
MutPred
Gain of phosphorylation at A2 (P = 0.018);Gain of phosphorylation at A2 (P = 0.018);Gain of phosphorylation at A2 (P = 0.018);Gain of phosphorylation at A2 (P = 0.018);Gain of phosphorylation at A2 (P = 0.018);Gain of phosphorylation at A2 (P = 0.018);
MVP
0.90
MPC
2.1
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
Publications
No publications associated with this variant yet.