rs1060501008
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_014191.4(SCN8A):c.1426A>C(p.Ser476Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,452,946 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
SCN8A
NM_014191.4 missense
NM_014191.4 missense
Scores
6
5
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, SCN8A
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN8A | NM_001330260.2 | c.1426A>C | p.Ser476Arg | missense_variant | 11/27 | ENST00000627620.5 | |
SCN8A | NM_014191.4 | c.1426A>C | p.Ser476Arg | missense_variant | 11/27 | ENST00000354534.11 | |
SCN8A | NM_001177984.3 | c.1426A>C | p.Ser476Arg | missense_variant | 11/26 | ||
SCN8A | NM_001369788.1 | c.1426A>C | p.Ser476Arg | missense_variant | 11/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN8A | ENST00000354534.11 | c.1426A>C | p.Ser476Arg | missense_variant | 11/27 | 1 | NM_014191.4 | P4 | |
SCN8A | ENST00000627620.5 | c.1426A>C | p.Ser476Arg | missense_variant | 11/27 | 5 | NM_001330260.2 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1452946Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1AN XY: 721828
GnomAD4 exome
AF:
AC:
3
AN:
1452946
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
721828
Gnomad4 AFR exome
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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 | Aug 16, 2016 | In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SCN8A-related disease. This sequence change replaces serine with arginine at codon 476 of the SCN8A protein (p.Ser476Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T;.;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
Polyphen
0.99, 0.88
.;D;.;.;P;.;.
Vest4
0.52, 0.51, 0.49, 0.57, 0.45
MutPred
Loss of phosphorylation at S476 (P = 7e-04);Loss of phosphorylation at S476 (P = 7e-04);Loss of phosphorylation at S476 (P = 7e-04);Loss of phosphorylation at S476 (P = 7e-04);Loss of phosphorylation at S476 (P = 7e-04);Loss of phosphorylation at S476 (P = 7e-04);.;
MVP
0.91
MPC
1.5
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