rs202151337

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_ModeratePP5_Moderate

The NM_001330260.2(SCN8A):​c.5302A>G​(p.Asn1768Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. N1768N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

SCN8A
NM_001330260.2 missense

Scores

16
2
1

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:2

Conservation

PhyloP100: 7.52
Variant links:
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 9 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001330260.2
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.909
PP5
Variant 12-51806788-A-G is Pathogenic according to our data. Variant chr12-51806788-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 30123.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-51806788-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN8ANM_001330260.2 linkc.5302A>G p.Asn1768Asp missense_variant Exon 27 of 27 ENST00000627620.5 NP_001317189.1 Q9UQD0-2Q6B4S4
SCN8ANM_014191.4 linkc.5302A>G p.Asn1768Asp missense_variant Exon 27 of 27 ENST00000354534.11 NP_055006.1 Q9UQD0-1
SCN8ANM_001177984.3 linkc.5179A>G p.Asn1727Asp missense_variant Exon 26 of 26 NP_001171455.1 Q9UQD0-5
SCN8ANM_001369788.1 linkc.5179A>G p.Asn1727Asp missense_variant Exon 26 of 26 NP_001356717.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN8AENST00000354534.11 linkc.5302A>G p.Asn1768Asp missense_variant Exon 27 of 27 1 NM_014191.4 ENSP00000346534.4 Q9UQD0-1
SCN8AENST00000627620.5 linkc.5302A>G p.Asn1768Asp missense_variant Exon 27 of 27 5 NM_001330260.2 ENSP00000487583.2 Q9UQD0-2
SCN8AENST00000599343.5 linkc.5335A>G p.Asn1779Asp missense_variant Exon 26 of 26 5 ENSP00000476447.3 Q9UQD0-3
SCN8AENST00000355133.7 linkc.5179A>G p.Asn1727Asp missense_variant Exon 25 of 25 1 ENSP00000347255.4 Q9UQD0-5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2Other:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 13 Pathogenic:1Other:1
-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Mar 09, 2012
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Sep 23, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces asparagine with aspartic acid at codon 1768 of the SCN8A protein (p.Asn1768Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with epileptic encephalopathy (PMID: 22365152, 29186148). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30123). This variant has been reported to affect SCN8A protein function (PMID: 22365152, 25227913, 28676574). For these reasons, this variant has been classified as Pathogenic. -

Complex neurodevelopmental disorder Other:1
-
Channelopathy-Associated Epilepsy Research Center
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.20
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
D;.;.;.;.
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;.;D;D
M_CAP
Pathogenic
0.82
D
MetaRNN
Pathogenic
0.91
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.7
H;.;.;.;H
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-4.7
D;D;.;.;.
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D;D;.;.;.
Sift4G
Uncertain
0.0090
D;D;D;D;D
Polyphen
1.0
D;.;.;.;.
Vest4
0.82
MutPred
0.44
Gain of disorder (P = 0.128);.;.;.;Gain of disorder (P = 0.128);
MVP
0.96
MPC
1.7
ClinPred
0.99
D
GERP RS
5.1
Varity_R
0.96
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs202151337; hg19: chr12-52200572; API