chr12-51765675-G-A

Position:

• chr12-51765675-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_014191.4(SCN8A):​c.2549G>A​(p.Arg850Gln) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R850E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN8A NM_014191.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:2
• Conservation: PhyloP100: 9.99

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 19 ACMG points.

• PM1: In a repeat II (size 272) in uniprot entity SCN8A_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_014191.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 12-51765675-G-A is Pathogenic according to our data. Variant chr12-51765675-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 135651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.2549G>A	p.Arg850Gln	missense_variant	16/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.2549G>A	p.Arg850Gln	missense_variant	16/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.2549G>A	p.Arg850Gln	missense_variant	16/26		NP_001171455.1
SCN8A	NM_001369788.1	c.2549G>A	p.Arg850Gln	missense_variant	16/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.2549G>A	p.Arg850Gln	missense_variant	16/27	1	NM_014191.4	ENSP00000346534	P4
SCN8A	ENST00000627620.5	c.2549G>A	p.Arg850Gln	missense_variant	16/27	5	NM_001330260.2	ENSP00000487583	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1379146 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 679788

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.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 13 Pathogenic:7 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	research	Bruce Lefroy Centre, Murdoch Childrens Research Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Feb 05, 2013	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Mendelics	Feb 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	May 30, 2017	- -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 29, 2024	This variant is interpreted as Pathogenic for developmental and epileptic encephalopathy 13. This missense change is absent from large population cohorts (gnomAD v4.1.0 PM2_supporting); it has been observed as de novo variant in multiple unrelated individuals with epileptic encephalopathies (PMID: 25785782; 27779742; 29720203 PS2_strong and PS4_moderate); computational evidence strongly support a damaging effect on gene or gene product (Revel 0,987 PP3_Strong); functional assays show that the variant affects channel properties and function (PMID: 31715021 PS3_moderate). -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2022	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; This variant is associated with the following publications: (PMID: 29720203, 25785782, 25326637, 29186148, 27779742, 28923014, 31302675, 32090326, 32139178, 32695065, 32371413, 34426522, 32969205) -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	Aug 17, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	Jul 20, 2022	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2018

The p.R850Q pathogenic mutation (also known as c.2549G>A), located in coding exon 15 of the SCN8A gene, results from a G to A substitution at nucleotide position 2549. The arginine at codon 850 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected as de novo occurrences in several individuals with early infantile epileptic encephalopathy (EIEE) and non specific epileptic encephalopathies as well as in one individual with severe childhood epilepsy (Kong W et al. Epilepsia, 2015 Mar;56:431-8; Zhang Q et al. Clin. Genet., 2017 May;91:717-724; Stank D et al. Orphanet J Rare Dis, 2018 May;13:71; Zhu X et al. PLoS Genet., 2017 Nov;13:e1007104). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 20, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 850 of the SCN8A protein (p.Arg850Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 25785782, 27779742, 28923014, 29186148, 29720203). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 135651). 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%. This variant disrupts the p.Arg850 amino acid residue in SCN8A. Other variant(s) that disrupt this residue have been observed in individuals with SCN8A-related conditions (PMID: 30171078), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Cognitive impairment with or without cerebellar ataxia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

May 02, 2023

- -

West syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Dec 15, 2023

- -

Cognitive impairment with or without cerebellar ataxia;C3281191:Developmental and epileptic encephalopathy, 13;C4310728:Seizures, benign familial infantile, 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Sep 29, 2018

[ACMG/AMP: PS2, PM1, PM2, PP2, PP3, PP5] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is absent from or rarely observed in large-scale population databases [PM2], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5]. -

Complex neurodevelopmental disorder Other:1

not provided, no classification provided

literature only

Channelopathy-Associated Epilepsy Research Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;.;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.7	H;H;H;.;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.9	D;D;D;.;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;D;.;.
Sift4G	Uncertain	0.015	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.96
MutPred		0.89		Loss of MoRF binding (P = 0.0367);Loss of MoRF binding (P = 0.0367);Loss of MoRF binding (P = 0.0367);.;Loss of MoRF binding (P = 0.0367);
MVP		1.0
MPC		3.4
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.92
gMVP		1.0

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: rs587780586; hg19: chr12-52159459;