rs886041670

chr12-51790419-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_014191.4(SCN8A):c.4441A>G(p.Met1481Val) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN8A NM_014191.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 9.32

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 Likely_pathogenic. Variant got 8 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, 6 uncertain in NM_014191.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN8A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874
• PP5: Variant 12-51790419-A-G is Pathogenic according to our data. Variant chr12-51790419-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 280470.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.4441A>G	p.Met1481Val	missense_variant	25/27	ENST00000627620.5
SCN8A	NM_014191.4	c.4441A>G	p.Met1481Val	missense_variant	25/27	ENST00000354534.11
SCN8A	NM_001177984.3	c.4318A>G	p.Met1440Val	missense_variant	24/26
SCN8A	NM_001369788.1	c.4318A>G	p.Met1440Val	missense_variant	24/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.4441A>G	p.Met1481Val	missense_variant	25/27	1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.4441A>G	p.Met1481Val	missense_variant	25/27	5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000548

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26029160) -

Focal impaired awareness seizure Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

New York Genome Center

Jan 10, 2020

The heterozygous missense p.Met1481Val variant is absent from the gnomAD database. The variant has been submitted to the ClinVar database by other genetic testing laboratories, including one instance where a laboratory has reported this variant as confirmed de novo in a patient with seizures [Variation ID: 280470]. Most of the SCN8A pathogenic variants reported to-date are missense and de novo [NBK379665; PMID: 25568300]. The p.Met1481Val variant is predicted deleterious by multiple in silico prediction tools. The affected residue is evolutionarily conserved and is predicted to be located in the cytoplasmic loop between the third and fourth homologous repeat domains [PMID: 26029160]. Based on available evidence along with the observation that the proband has inherited this variant from her affected mother, the p.Met1481Val variant in the SCN8A gene is assessed as likely pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 24, 2022

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. 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: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 280470). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1481 of the SCN8A protein (p.Met1481Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;.;.;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;.;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.7	H;.;.;.;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.7	D;D;D;.;.
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		0.91	P;.;.;.;.
Vest4		0.79
MutPred		0.29		Loss of disorder (P = 0.0801);.;.;.;Loss of disorder (P = 0.0801);
MVP		0.98
MPC		1.4
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.79
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: rs886041670; hg19: chr12-52184203;