rs758253791
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_014191.4(SCN8A):c.2003C>T(p.Thr668Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000254 in 1,575,754 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. T668A) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
SCN8A
NM_014191.4 missense
NM_014191.4 missense
Scores
6
9
4
Clinical Significance
Conservation
PhyloP100: 5.84
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 39 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN8A | NM_001330260.2 | c.2003C>T | p.Thr668Ile | missense_variant | 13/27 | ENST00000627620.5 | |
SCN8A | NM_014191.4 | c.2003C>T | p.Thr668Ile | missense_variant | 13/27 | ENST00000354534.11 | |
SCN8A | NM_001177984.3 | c.2003C>T | p.Thr668Ile | missense_variant | 13/26 | ||
SCN8A | NM_001369788.1 | c.2003C>T | p.Thr668Ile | missense_variant | 13/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN8A | ENST00000354534.11 | c.2003C>T | p.Thr668Ile | missense_variant | 13/27 | 1 | NM_014191.4 | P4 | |
SCN8A | ENST00000627620.5 | c.2003C>T | p.Thr668Ile | missense_variant | 13/27 | 5 | NM_001330260.2 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000664 AC: 1AN: 150584Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000137 AC: 3AN: 218480Hom.: 0 AF XY: 0.00000843 AC XY: 1AN XY: 118636
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GnomAD4 exome AF: 0.0000274 AC: 39AN: 1425170Hom.: 0 Cov.: 32 AF XY: 0.0000198 AC XY: 14AN XY: 707702
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GnomAD4 genome ? AF: 0.00000664 AC: 1AN: 150584Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1AN XY: 73366
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1Other: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 | Oct 14, 2023 | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 668 of the SCN8A protein (p.Thr668Ile). This variant is present in population databases (rs758253791, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of SCN8A-related conditions (PMID: 25849321; Invitae). ClinVar contains an entry for this variant (Variation ID: 253283). 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. 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. - |
Developmental and epileptic encephalopathy, 13 Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;.;T;T;T
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M;.;M;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;.;.;.
REVEL
Pathogenic
Sift
Benign
D;D;D;.;.;.
Sift4G
Benign
T;T;T;T;T;D
Polyphen
P;.;.;P;.;.
Vest4
MutPred
Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);.;Gain of loop (P = 0.0166);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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