rs773966403

Variant names:

• chr12-51807280-C-T
• rs773966403
• NM_001330260.2:c.5794C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001330260.2(SCN8A):​c.5794C>T​(p.Arg1932Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 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. R1932P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: SCN8A NM_001330260.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.978

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_benign. Variant got -5 ACMG points.

• 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, 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19956082).
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.5794C>T	p.Arg1932Trp	missense_variant	Exon 27 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.5794C>T	p.Arg1932Trp	missense_variant	Exon 27 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.5671C>T	p.Arg1891Trp	missense_variant	Exon 26 of 26		NP_001171455.1
SCN8A	NM_001369788.1	c.5671C>T	p.Arg1891Trp	missense_variant	Exon 26 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.5794C>T	p.Arg1932Trp	missense_variant	Exon 27 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.5794C>T	p.Arg1932Trp	missense_variant	Exon 27 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.5827C>T	p.Arg1943Trp	missense_variant	Exon 26 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.5671C>T	p.Arg1891Trp	missense_variant	Exon 25 of 25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 249088 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135154

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461702 Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 727128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Dec 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1932 of the SCN8A protein (p.Arg1932Trp). This variant is present in population databases (rs773966403, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. ClinVar contains an entry for this variant (Variation ID: 461349). 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 not expected to disrupt SCN8A protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;.;.;.;.
Eigen	Benign	0.077
Eigen_PC	Benign	0.069
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;.;D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	0.81	L;.;.;.;L
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.7	N;N;.;.;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.0050	D;D;.;.;.
Sift4G	Uncertain	0.017	D;D;D;D;D
Polyphen		0.96	D;.;.;.;.
Vest4		0.19
MutPred		0.21		Loss of phosphorylation at T1930 (P = 0.0689);.;.;.;Loss of phosphorylation at T1930 (P = 0.0689);
MVP		0.73
MPC		1.7
ClinPred		0.47	T
GERP RS		1.5
Varity_R		0.075
gMVP		0.51

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: rs773966403; hg19: chr12-52201064;