chr12-51786554-G-T

Position:

• chr12-51786554-G-T

Variant summary

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

The NM_014191.4(SCN8A):​c.3955G>T​(p.Ala1319Ser) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A1319A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN8A NM_014191.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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 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, 0.92
• PP5: Variant 12-51786554-G-T is Pathogenic according to our data. Variant chr12-51786554-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 207117.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.3955G>T	p.Ala1319Ser	missense_variant	22/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.3955G>T	p.Ala1319Ser	missense_variant	22/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.3832G>T	p.Ala1278Ser	missense_variant	21/26		NP_001171455.1
SCN8A	NM_001369788.1	c.3832G>T	p.Ala1278Ser	missense_variant	21/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.3955G>T	p.Ala1319Ser	missense_variant	22/27	1	NM_014191.4	ENSP00000346534	P4
SCN8A	ENST00000627620.5	c.3955G>T	p.Ala1319Ser	missense_variant	22/27	5	NM_001330260.2	ENSP00000487583	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 09, 2020

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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"). This variant has been observed in individual(s) with clinical features of SCN8A-related conditions (PMID: 29655203, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207117). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with serine at codon 1319 of the SCN8A protein (p.Ala1319Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 04, 2013

p.Ala1319Ser (GCC>TCC): c.3955 G>T in exon 22 of the SCN8A gene (NM_014191.3).The Ala1319Ser missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. 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. This variant is a non-conservative amino acid substitution of a non-polar Alanine residue with a polar Serine residue. This variant occurs at a highly conserved position between the S4 and S5 segments in the third transmembrane domain of the SCN8A protein and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, to our knowledge, other missense mutations in the same region of the protein have not been reported in association with epilepsy. This variant has been observed de novo without verified parentage. The variant is found in INFANT-EPI panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;.;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;.;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M;.;.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.9	D;D;D;.;.
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D;D;.;.
Sift4G	Uncertain	0.044	D;T;T;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.81
MutPred		0.77		Loss of methylation at R1314 (P = 0.1188);.;.;.;Loss of methylation at R1314 (P = 0.1188);
MVP		0.97
MPC		2.2
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.83
gMVP		0.95

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: rs796053214; hg19: chr12-52180338;