rs879255652

Positions:

• chr12-51790425-G-A
• chr12-51790425-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_014191.4(SCN8A):​c.4447G>A​(p.Glu1483Lys) 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. 12/21 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. E1483D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN8A NM_014191.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:2
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_014191.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN8A. . Gene score misZ 0.78755 (greater than the threshold 3.09). Trascript score misZ 10.278 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.912
• PP5: Variant 12-51790425-G-A is Pathogenic according to our data. Variant chr12-51790425-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 253195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.4447G>A	p.Glu1483Lys	missense_variant	25/27	ENST00000627620.5
SCN8A	NM_014191.4	c.4447G>A	p.Glu1483Lys	missense_variant	25/27	ENST00000354534.11
SCN8A	NM_001177984.3	c.4324G>A	p.Glu1442Lys	missense_variant	24/26
SCN8A	NM_001369788.1	c.4324G>A	p.Glu1442Lys	missense_variant	24/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.4447G>A	p.Glu1483Lys	missense_variant	25/27	1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.4447G>A	p.Glu1483Lys	missense_variant	25/27	5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1456062 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000549

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Seizures, benign familial infantile, 5 Pathogenic:3

Pathogenic, criteria provided, single submitter	research	University of British Columbia, BC Children's Hospital	Aug 30, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 22, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 18, 2022	- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 19, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1483 of the SCN8A protein (p.Glu1483Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of SCN8A-related conditions (PMID: 26677014, 30185235). It has also been observed to segregate with disease in related individuals. This variant is also known as p.E1442K. ClinVar contains an entry for this variant (Variation ID: 253195). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN8A protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN8A function (PMID: 30615093). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 10, 2022

Published functional studies demonstrate a damaging effect indicating that the E1483K variant alters sodium channel properties (Liu et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 32090326, 30615093, 27210545, 27270488, 26677014, 30185235, 29263050, 31904124, 26029160) -

Epilepsy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Feb 25, 2021

The variant chr12-52184209-G-A, SCN8A(NM_014191.4):c.4447G>A,p.(Glu1483Lys) was identified in an individual with Epilepsy. Inheritance was maternal (heterozygous). The variant was reviewed according to current ACMG recommendations and classified as Pathogenic (criteria: PP1_Strong, PS3_Moderate, PS4_Moderate, PM2_Supporting, PP3_Supporting). -

Developmental and epileptic encephalopathy, 13 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Complex neurodevelopmental disorder Other:1

not provided, no classification provided

literature only

Channelopathy-Associated Epilepsy Research Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;.;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;.;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.;.;.;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.7	D;D;D;.;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D;.;.
Sift4G	Uncertain	0.049	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.85
MutPred		0.46		Gain of MoRF binding (P = 0.0105);.;.;.;Gain of MoRF binding (P = 0.0105);
MVP		0.98
MPC		2.1
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.83
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs879255652; hg19: chr12-52184209;