rs1057518487

Positions:

• chr12-51688775-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 PP3 PP5_Very_Strong

The NM_014191.4(SCN8A):​c.632T>C​(p.Val211Ala) 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: 32)
• Consequence: SCN8A NM_014191.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 8.02

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]

SCN8A (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 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, 0.772
• PP5: Variant 12-51688775-T-C is Pathogenic according to our data. Variant chr12-51688775-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 373565.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_014191.4	c.632T>C	p.Val211Ala	missense_variant	6/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001330260.2	c.615-230T>C		intron_variant		ENST00000627620.5	NP_001317189.1
SCN8A	NM_001177984.3	c.632T>C	p.Val211Ala	missense_variant	6/26		NP_001171455.1
SCN8A	NM_001369788.1	c.615-230T>C		intron_variant			NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.632T>C	p.Val211Ala	missense_variant	6/27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000599343.5	c.632T>C	p.Val211Ala	missense_variant	5/26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.632T>C	p.Val211Ala	missense_variant	5/25	1		ENSP00000347255.4
SCN8A	ENST00000627620.5	c.615-230T>C		intron_variant		5	NM_001330260.2	ENSP00000487583.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2016	A novel V211A variant that is likely pathogenic has been identified in the SCN8A gene. The V211A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V211A variant is a conservative amino acid substitution that occurs at a conserved position predicted to alter a residue within the S3 of the helical transmembrane region of repeat I, and in silico analysis predicts this variant is probably damaging to the protein structure/function. It has been identified as a confirmed de novo variant in a patient referred for testing at GeneDx. Therefore, we interpret V211A as a likely pathogenic variant. -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Jun 13, 2017	- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 19, 2018

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 to be de novo in an individual affected with early infantile epileptic encephalopathy (PMID: 29121005). ClinVar contains an entry for this variant (Variation ID: 373565). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with alanine at codon 211 of the SCN8A protein (p.Val211Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	T;T;.;T
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;M;M;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.9	D;D;D;.
REVEL	Pathogenic	0.85
Sift	Benign	0.040	D;D;D;.
Sift4G	Uncertain	0.019	D;D;D;D
Polyphen		0.91	P;.;.;.
Vest4		0.64
MutPred		0.73		Loss of stability (P = 0.0673);Loss of stability (P = 0.0673);Loss of stability (P = 0.0673);Loss of stability (P = 0.0673);
MVP		0.85
MPC		2.3
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.51
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057518487; hg19: chr12-52082559;