rs1057518293

Positions:

• chr12-51699623-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_001330260.2(SCN8A):​c.760G>A​(p.Val254Met) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN8A NM_001330260.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• 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]

SCN8A (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• 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 10.436 (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, 0.936
• PP5: Variant 12-51699623-G-A is Pathogenic according to our data. Variant chr12-51699623-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 373224.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.760G>A	p.Val254Met	missense_variant	7/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.760G>A	p.Val254Met	missense_variant	7/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.760G>A	p.Val254Met	missense_variant	7/26		NP_001171455.1
SCN8A	NM_001369788.1	c.760G>A	p.Val254Met	missense_variant	7/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.760G>A	p.Val254Met	missense_variant	7/27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.760G>A	p.Val254Met	missense_variant	7/27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.760G>A	p.Val254Met	missense_variant	6/26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.760G>A	p.Val254Met	missense_variant	6/25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 254 of the SCN8A protein (p.Val254Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 373224). 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%. For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 28, 2016

The V254M variant in the SCN8A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V254M variant was not observed in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the V254M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, we interpret V254M as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;D;.;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;.;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	.;H;H;H;H;H;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.9	.;D;D;D;.;.;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	.;D;D;D;.;.;.
Sift4G	Pathogenic	0.0010	.;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;.;.;D;.;.
Vest4		0.80, 0.79, 0.80, 0.81, 0.79
MutPred		0.71		Loss of ubiquitination at K249 (P = 0.0957);Loss of ubiquitination at K249 (P = 0.0957);Loss of ubiquitination at K249 (P = 0.0957);Loss of ubiquitination at K249 (P = 0.0957);Loss of ubiquitination at K249 (P = 0.0957);Loss of ubiquitination at K249 (P = 0.0957);.;
MVP		1.0
MPC		2.1
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.90
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

Other links and lift over

dbSNP: rs1057518293; hg19: chr12-52093407;