rs576362165

Positions:

• chr12-51706554-C-A
• chr12-51706554-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The ENST00000354534.11(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 ENST00000354534.11 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.12

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 Uncertain_significance. Variant got 3 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 10.278 (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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.1474C>A	p.Arg492Ser	missense_variant	11/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.1474C>A	p.Arg492Ser	missense_variant	11/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.1474C>A	p.Arg492Ser	missense_variant	11/26		NP_001171455.1
SCN8A	NM_001369788.1	c.1474C>A	p.Arg492Ser	missense_variant	11/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.1474C>A	p.Arg492Ser	missense_variant	11/27	1	NM_014191.4	ENSP00000346534	P4
SCN8A	ENST00000627620.5	c.1474C>A	p.Arg492Ser	missense_variant	11/27	5	NM_001330260.2	ENSP00000487583	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000421 AC: 1 AN: 237448 Hom.: 0 AF XY: 0.00000778 AC XY: 1 AN XY: 128514

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 SAS 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

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: 0.00000361

Gnomad4 OTH exome AF: 0.00

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

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2022

This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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 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). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 21, 2022

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;.
MutationTaster	Benign	1.0	D;D;D
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

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: rs576362165; hg19: chr12-52100338;