12-51769330-A-G
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_001330260.2(SCN8A):c.3367A>G(p.Lys1123Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,429,688 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: 7.0e-7 ( 0 hom. )
Consequence
SCN8A
NM_001330260.2 missense
NM_001330260.2 missense
Scores
4
10
5
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 in the SCN8A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 213 curated pathogenic missense variants (we use a threshold of 10). The gene has 45 curated benign missense variants. Gene score misZ: 0.78755 (below the threshold of 3.09). Trascript score misZ: 10.436 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN8A | NM_001330260.2 | c.3367A>G | p.Lys1123Glu | missense_variant | Exon 17 of 27 | ENST00000627620.5 | NP_001317189.1 | |
SCN8A | NM_014191.4 | c.3367A>G | p.Lys1123Glu | missense_variant | Exon 17 of 27 | ENST00000354534.11 | NP_055006.1 | |
SCN8A | NM_001177984.3 | c.3367A>G | p.Lys1123Glu | missense_variant | Exon 17 of 26 | NP_001171455.1 | ||
SCN8A | NM_001369788.1 | c.3367A>G | p.Lys1123Glu | missense_variant | Exon 17 of 26 | NP_001356717.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN8A | ENST00000354534.11 | c.3367A>G | p.Lys1123Glu | missense_variant | Exon 17 of 27 | 1 | NM_014191.4 | ENSP00000346534.4 | ||
SCN8A | ENST00000627620.5 | c.3367A>G | p.Lys1123Glu | missense_variant | Exon 17 of 27 | 5 | NM_001330260.2 | ENSP00000487583.2 | ||
SCN8A | ENST00000599343.5 | c.3400A>G | p.Lys1134Glu | missense_variant | Exon 16 of 26 | 5 | ENSP00000476447.3 | |||
SCN8A | ENST00000355133.7 | c.3367A>G | p.Lys1123Glu | missense_variant | Exon 16 of 25 | 1 | ENSP00000347255.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.99e-7 AC: 1AN: 1429688Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1AN XY: 706160
GnomAD4 exome
AF:
AC:
1
AN:
1429688
Hom.:
Cov.:
30
AF XY:
AC XY:
1
AN XY:
706160
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
not provided Uncertain:1
Jun 17, 2022
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.;.
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;.;T;T
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;.;M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;.;.
REVEL
Pathogenic
Sift
Benign
D;D;D;.;.
Sift4G
Benign
T;T;T;T;T
Polyphen
D;.;.;.;.
Vest4
MutPred
Loss of ubiquitination at K1123 (P = 0.0047);Loss of ubiquitination at K1123 (P = 0.0047);Loss of ubiquitination at K1123 (P = 0.0047);.;Loss of ubiquitination at K1123 (P = 0.0047);
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
Publications
No publications associated with this variant yet.