rs1359860813
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_014191.4(SCN8A):c.1817G>A(p.Arg606Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000752 in 1,595,942 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R606W) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000069 ( 0 hom. )
Consequence
SCN8A
NM_014191.4 missense
NM_014191.4 missense
Scores
3
7
3
Clinical Significance
Conservation
PhyloP100: 6.44
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 Likely_benign. Variant got -3 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, SCN8A
BS2
?
High AC in GnomAdExome4 at 10 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN8A | NM_001330260.2 | c.1817G>A | p.Arg606Gln | missense_variant | 12/27 | ENST00000627620.5 | |
SCN8A | NM_014191.4 | c.1817G>A | p.Arg606Gln | missense_variant | 12/27 | ENST00000354534.11 | |
SCN8A | NM_001177984.3 | c.1817G>A | p.Arg606Gln | missense_variant | 12/26 | ||
SCN8A | NM_001369788.1 | c.1817G>A | p.Arg606Gln | missense_variant | 12/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN8A | ENST00000354534.11 | c.1817G>A | p.Arg606Gln | missense_variant | 12/27 | 1 | NM_014191.4 | P4 | |
SCN8A | ENST00000627620.5 | c.1817G>A | p.Arg606Gln | missense_variant | 12/27 | 5 | NM_001330260.2 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152152Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000476 AC: 1AN: 210122Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 114954
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GnomAD4 exome AF: 0.00000693 AC: 10AN: 1443790Hom.: 0 Cov.: 31 AF XY: 0.00000698 AC XY: 5AN XY: 716804
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152152Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74324
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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 | Jun 27, 2023 | 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: 530416). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 606 of the SCN8A protein (p.Arg606Gln). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;.;D;D;D
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
0.95, 1.0
.;P;.;.;D;.;.
Vest4
0.71, 0.74, 0.75, 0.77, 0.70
MutPred
Loss of MoRF binding (P = 0.0286);Loss of MoRF binding (P = 0.0286);Loss of MoRF binding (P = 0.0286);Loss of MoRF binding (P = 0.0286);Loss of MoRF binding (P = 0.0286);Loss of MoRF binding (P = 0.0286);.;
MVP
0.93
MPC
1.6
ClinPred
D
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at