rs879255697

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_001330260.2(SCN8A):​c.779T>C​(p.Phe260Ser) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F260V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

SCN8A
NM_001330260.2 missense

Scores

17
1
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 8.02

Publications

10 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: Pathogenic. The variant received 13 ACMG points.

PM1
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001330260.2
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-51699641-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1803066.Status of the report is criteria_provided_single_submitter, 1 stars.
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.96
PP5
Variant 12-51699642-T-C is Pathogenic according to our data. Variant chr12-51699642-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 253279.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN8ANM_001330260.2 linkc.779T>C p.Phe260Ser missense_variant Exon 7 of 27 ENST00000627620.5 NP_001317189.1 Q9UQD0-2Q6B4S4
SCN8ANM_014191.4 linkc.779T>C p.Phe260Ser missense_variant Exon 7 of 27 ENST00000354534.11 NP_055006.1 Q9UQD0-1
SCN8ANM_001177984.3 linkc.779T>C p.Phe260Ser missense_variant Exon 7 of 26 NP_001171455.1 Q9UQD0-5
SCN8ANM_001369788.1 linkc.779T>C p.Phe260Ser missense_variant Exon 7 of 26 NP_001356717.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN8AENST00000354534.11 linkc.779T>C p.Phe260Ser missense_variant Exon 7 of 27 1 NM_014191.4 ENSP00000346534.4 Q9UQD0-1
SCN8AENST00000627620.5 linkc.779T>C p.Phe260Ser missense_variant Exon 7 of 27 5 NM_001330260.2 ENSP00000487583.2 Q9UQD0-2
SCN8AENST00000599343.5 linkc.779T>C p.Phe260Ser missense_variant Exon 6 of 26 5 ENSP00000476447.3 Q9UQD0-3
SCN8AENST00000355133.7 linkc.779T>C p.Phe260Ser missense_variant Exon 6 of 25 1 ENSP00000347255.4 Q9UQD0-5

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy Pathogenic:1
Jan 24, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces phenylalanine with serine at codon 260 of the SCN8A protein (p.Phe260Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (PMID: 25568300, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 253279). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. -

Developmental and epileptic encephalopathy, 13 Other:1
-
GeneReviews
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
1.0
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
.;D;.;.;.;.;.
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D;D;.;D;D;D
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.3
.;H;H;H;H;H;.
PhyloP100
8.0
PrimateAI
Pathogenic
0.93
D
PROVEAN
Pathogenic
-7.8
.;D;D;D;.;.;D
REVEL
Pathogenic
0.99
Sift
Pathogenic
0.0
.;D;D;D;.;.;D
Sift4G
Pathogenic
0.0
.;D;D;D;D;D;D
Polyphen
0.92, 1.0
.;P;.;.;D;.;.
Vest4
0.92, 0.97, 0.97, 0.98, 0.97
MutPred
0.80
Loss of stability (P = 0.0539);Loss of stability (P = 0.0539);Loss of stability (P = 0.0539);Loss of stability (P = 0.0539);Loss of stability (P = 0.0539);Loss of stability (P = 0.0539);.;
MVP
0.99
MPC
2.7
ClinPred
1.0
D
GERP RS
4.5
Varity_R
0.98
gMVP
0.98
Mutation Taster
=2/98
disease causing (ClinVar)

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: rs879255697; hg19: chr12-52093426; API