NM_001330260.2:c.1474C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

The NM_001330260.2(SCN8A):​c.1474C>A​(p.Arg492Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,455,360 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. R492H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SCN8A
NM_001330260.2 missense

Scores

8
9
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.12

Publications

0 publications found
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]
SCN8A Gene-Disease associations (from GenCC):
  • complex neurodevelopmental disorder
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • developmental and epileptic encephalopathy, 13
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
  • cognitive impairment with or without cerebellar ataxia
    Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • seizures, benign familial infantile, 5
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • benign familial infantile epilepsy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • infantile convulsions and choreoathetosis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • undetermined early-onset epileptic encephalopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • myoclonus, familial, 2
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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, developmental and epileptic encephalopathy, 13, undetermined early-onset epileptic encephalopathy, benign familial infantile epilepsy, complex neurodevelopmental disorder, seizures, benign familial infantile, 5, cognitive impairment with or without cerebellar ataxia, infantile convulsions and choreoathetosis.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN8ANM_001330260.2 linkc.1474C>A p.Arg492Ser missense_variant Exon 11 of 27 ENST00000627620.5 NP_001317189.1 Q9UQD0-2Q6B4S4
SCN8ANM_014191.4 linkc.1474C>A p.Arg492Ser missense_variant Exon 11 of 27 ENST00000354534.11 NP_055006.1 Q9UQD0-1
SCN8ANM_001177984.3 linkc.1474C>A p.Arg492Ser missense_variant Exon 11 of 26 NP_001171455.1 Q9UQD0-5
SCN8ANM_001369788.1 linkc.1474C>A p.Arg492Ser missense_variant Exon 11 of 26 NP_001356717.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN8AENST00000354534.11 linkc.1474C>A p.Arg492Ser missense_variant Exon 11 of 27 1 NM_014191.4 ENSP00000346534.4 Q9UQD0-1
SCN8AENST00000627620.5 linkc.1474C>A p.Arg492Ser missense_variant Exon 11 of 27 5 NM_001330260.2 ENSP00000487583.2 Q9UQD0-2
SCN8AENST00000599343.5 linkc.1474C>A p.Arg492Ser missense_variant Exon 10 of 26 5 ENSP00000476447.3 Q9UQD0-3
SCN8AENST00000355133.7 linkc.1474C>A p.Arg492Ser missense_variant Exon 10 of 25 1 ENSP00000347255.4 Q9UQD0-5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000421
AC:
1
AN:
237448
AF XY:
0.00000778
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000937
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000275
AC:
4
AN:
1455360
Hom.:
0
Cov.:
31
AF XY:
0.00000277
AC XY:
2
AN XY:
723260
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33326
American (AMR)
AF:
0.00
AC:
0
AN:
43780
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26000
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39488
South Asian (SAS)
AF:
0.00
AC:
0
AN:
84916
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53090
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
0.00000361
AC:
4
AN:
1108826
Other (OTH)
AF:
0.00
AC:
0
AN:
60170
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.463
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000434
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy Uncertain:1
Oct 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 492 of the SCN8A protein (p.Arg492Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1706670). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. -

not provided Uncertain:1
Mar 21, 2022
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the cytoplasmic loop between the first and second homologous domains; Missense variants in this gene are often considered pathogenic (HGMD) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.11
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.82
.;D;.;.;.;.;.
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.92
D;D;D;.;D;D;D
M_CAP
Pathogenic
0.48
D
MetaRNN
Uncertain
0.65
D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.79
D
MutationAssessor
Uncertain
2.6
.;M;M;M;M;M;.
PhyloP100
1.1
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-4.6
.;D;D;D;.;.;.
REVEL
Pathogenic
0.66
Sift
Uncertain
0.0050
.;D;D;D;.;.;.
Sift4G
Benign
0.13
.;T;T;T;T;T;T
Polyphen
1.0, 1.0
.;D;.;.;D;.;.
Vest4
0.59, 0.59, 0.60, 0.57, 0.53
MutPred
0.29
Gain of phosphorylation at R492 (P = 1e-04);Gain of phosphorylation at R492 (P = 1e-04);Gain of phosphorylation at R492 (P = 1e-04);Gain of phosphorylation at R492 (P = 1e-04);Gain of phosphorylation at R492 (P = 1e-04);Gain of phosphorylation at R492 (P = 1e-04);.;
MVP
0.92
MPC
2.2
ClinPred
0.98
D
GERP RS
4.2
Varity_R
0.73
gMVP
0.70
Mutation Taster
=21/79
disease causing

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

Other links and lift over

dbSNP: rs576362165; hg19: chr12-52100338; API