12-51794620-G-A
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP2
The NM_014191.4(SCN8A):c.4774G>A(p.Val1592Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1592L) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
SCN8A
NM_014191.4 missense
NM_014191.4 missense
Scores
10
4
5
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
In a repeat IV (size 297) in uniprot entity SCN8A_HUMAN there are 68 pathogenic changes around while only 13 benign (84%) in NM_014191.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-51794620-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 130249.Status of the report is criteria_provided_single_submitter, 1 stars.
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.4774G>A | p.Val1592Ile | missense_variant | 26/27 | ENST00000627620.5 | |
SCN8A | NM_014191.4 | c.4774G>A | p.Val1592Ile | missense_variant | 26/27 | ENST00000354534.11 | |
SCN8A | NM_001177984.3 | c.4651G>A | p.Val1551Ile | missense_variant | 25/26 | ||
SCN8A | NM_001369788.1 | c.4651G>A | p.Val1551Ile | missense_variant | 25/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN8A | ENST00000354534.11 | c.4774G>A | p.Val1592Ile | missense_variant | 26/27 | 1 | NM_014191.4 | P4 | |
SCN8A | ENST00000627620.5 | c.4774G>A | p.Val1592Ile | missense_variant | 26/27 | 5 | NM_001330260.2 | A1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 13 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 28, 2023 | Criteria applied: PS2_MOD,PM5,PM2_SUP,PP2,PP3 - |
Early infantile epileptic encephalopathy with suppression bursts Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 04, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;.;.;.;L
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N;.;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;T;.;.
Sift4G
Benign
T;T;T;T;T
Polyphen
D;.;.;.;.
Vest4
MutPred
Loss of catalytic residue at V1592 (P = 0.3344);.;.;.;Loss of catalytic residue at V1592 (P = 0.3344);
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