chr12-51788702-T-C

Position:

• chr12-51788702-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_014191.4(SCN8A):​c.4235T>C​(p.Phe1412Ser) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN8A NM_014191.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 7.91

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_pathogenic. Variant got 8 ACMG points.

• PM1: In a intramembrane_region Pore-forming (size 21) in uniprot entity SCN8A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_014191.4
• 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, 0.93
• PP5: Variant 12-51788702-T-C is Pathogenic according to our data. Variant chr12-51788702-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 523505.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.4235T>C	p.Phe1412Ser	missense_variant	23/27	ENST00000627620.5
SCN8A	NM_014191.4	c.4235T>C	p.Phe1412Ser	missense_variant	23/27	ENST00000354534.11
SCN8A	NM_001177984.3	c.4112T>C	p.Phe1371Ser	missense_variant	22/26
SCN8A	NM_001369788.1	c.4112T>C	p.Phe1371Ser	missense_variant	22/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.4235T>C	p.Phe1412Ser	missense_variant	23/27	1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.4235T>C	p.Phe1412Ser	missense_variant	23/27	5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Febrile seizure (within the age range of 3 months to 6 years);C0085583:Choreoathetosis;C0270612:Leukoencephalopathy;C0557874:Global developmental delay Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 26, 2018

This sequence change replaces phenylalanine with serine at codon 1412 of the SCN8A protein (p.Phe1412Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SCN8A-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Developmental and epileptic encephalopathy, 13 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 20, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;.;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D;.;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.;.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.2	D;D;D;.;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;.;.
Sift4G	Uncertain	0.031	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.89
MutPred		0.66		Loss of methylation at K1413 (P = 0.033);.;.;.;Loss of methylation at K1413 (P = 0.033);
MVP		0.99
MPC		2.8
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.93
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: rs1555228665; hg19: chr12-52182486;