NM_001330260.2:c.4423G>A

Variant names:

• chr12-51790401-G-A
• rs796053216
• NM_001330260.2:c.4423G>A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001330260.2(SCN8A):​c.4423G>A​(p.Gly1475Arg) 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN8A NM_001330260.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O: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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 12-51790401-G-A is Pathogenic according to our data. Variant chr12-51790401-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 207119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.4423G>A	p.Gly1475Arg	missense_variant	Exon 25 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.4423G>A	p.Gly1475Arg	missense_variant	Exon 25 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.4300G>A	p.Gly1434Arg	missense_variant	Exon 24 of 26		NP_001171455.1
SCN8A	NM_001369788.1	c.4300G>A	p.Gly1434Arg	missense_variant	Exon 24 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.4423G>A	p.Gly1475Arg	missense_variant	Exon 25 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.4423G>A	p.Gly1475Arg	missense_variant	Exon 25 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.4456G>A	p.Gly1486Arg	missense_variant	Exon 24 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.4300G>A	p.Gly1434Arg	missense_variant	Exon 23 of 25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1451118 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 721744

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

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN8A: PM1, PM2, PS4:Moderate, PP2, PP3, PP4, PS3:Supporting -

May 19, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29235621, 30776697, 27864847, 29128679, 28923014, 29429461, 30171078, 30615093, 31402610, 32090326, 32040247) -

Developmental and epileptic encephalopathy, 13 Pathogenic:2

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

he variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000207119, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.75, 3CNET: 0.972, PP3_P). A missense variant is a common mechanism associated with Developmental and epileptic encephalopathy 13 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). TTherefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Oct 29, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Nov 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1475 of the SCN8A protein (p.Gly1475Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 27864847, 28923014, 30171078). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207119). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN8A protein function. Experimental studies have shown that this missense change affects SCN8A function (PMID: 30615093). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Epileptic encephalopathy Pathogenic:1

Nov 16, 2016

Neurogenetics Laboratory - MEYER, AOU Meyer

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epilepsy Pathogenic:1

Nov 06, 2017

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified in a mosaic state in a young female patient with epilepsy. -

Complex neurodevelopmental disorder Other:1

-

Channelopathy-Associated Epilepsy Research Center

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;.;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;T;.;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.8	M;.;.;.;M
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.4	D;D;D;.;.
REVEL	Pathogenic	0.75
Sift	Benign	0.051	T;T;D;.;.
Sift4G	Uncertain	0.060	T;T;T;T;T
Polyphen		0.74	P;.;.;.;.
Vest4		0.89
MutPred		0.39		Gain of catalytic residue at G1475 (P = 0.0387);.;.;.;Gain of catalytic residue at G1475 (P = 0.0387);
MVP		0.93
MPC		1.5
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.39
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs796053216; hg19: chr12-52184185; COSMIC: COSV61993169; COSMIC: COSV61993169;