12-51807101-G-T

Position:

• chr12-51807101-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001330260.2(SCN8A):​c.5615G>T​(p.Arg1872Leu) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1872Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN8A NM_001330260.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 8.15

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 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-51807101-G-A is described in Lovd as [Pathogenic].
• 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 10.436 (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, 0.851
• PP5: Variant 12-51807101-G-T is Pathogenic according to our data. Variant chr12-51807101-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 207132.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.5615G>T	p.Arg1872Leu	missense_variant	27/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.5615G>T	p.Arg1872Leu	missense_variant	27/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.5492G>T	p.Arg1831Leu	missense_variant	26/26		NP_001171455.1
SCN8A	NM_001369788.1	c.5492G>T	p.Arg1831Leu	missense_variant	26/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.5615G>T	p.Arg1872Leu	missense_variant	27/27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.5615G>T	p.Arg1872Leu	missense_variant	27/27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.5648G>T	p.Arg1883Leu	missense_variant	26/26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.5492G>T	p.Arg1831Leu	missense_variant	25/25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 17, 2022

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1872 of the SCN8A protein (p.Arg1872Leu). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1872 amino acid residue in SCN8A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25568300, 26647175, 26900580, 28387369). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SCN8A function (PMID: 26900580). 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"). ClinVar contains an entry for this variant (Variation ID: 207132). This missense change has been observed in individual(s) with autosomal dominant epilepsy and/or autosomal dominant epileptic encephalopathy with cerebellar atrophy (PMID: 26900580, 31402610). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 15, 2014

p.Arg1872Leu (CGG>CTG): c.5615 G>T in exon 27 of the SCN8A gene (NM_014191.3)The R1872L mutation has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. R1872L is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution alters a highly conserved position in the in the cytoplasmic domain after the 4th homologous repeat. In silico analysis predicts this substitution is probably damaging to the protein structure/function. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, it was previously identified at GeneDx as a de novo change in an individual with clinical features consistent with an SCN8A-related disorder. Although this mutation has not been reported previously to our knowledge, it is interpreted to be a disease-causing mutation. The variant is found in INFANT-EPI panel(s). -

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	0.95
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.;.;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;.;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;.;.;.;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.9	D;D;.;.;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;.;.;.
Sift4G	Uncertain	0.016	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.80
MutPred		0.44		Loss of disorder (P = 0.0373);.;.;.;Loss of disorder (P = 0.0373);
MVP		0.99
MPC		2.5
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.85
gMVP		0.96

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: rs796053229; hg19: chr12-52200885;