rs1555226186

Positions:

• chr12-51769330-A-C
• chr12-51769330-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The ENST00000354534.11(SCN8A):​c.3367A>C​(p.Lys1123Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1123E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN8A ENST00000354534.11 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.32

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 Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.3367A>C	p.Lys1123Gln	missense_variant	17/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.3367A>C	p.Lys1123Gln	missense_variant	17/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.3367A>C	p.Lys1123Gln	missense_variant	17/26		NP_001171455.1
SCN8A	NM_001369788.1	c.3367A>C	p.Lys1123Gln	missense_variant	17/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.3367A>C	p.Lys1123Gln	missense_variant	17/27	1	NM_014191.4	ENSP00000346534	P4
SCN8A	ENST00000627620.5	c.3367A>C	p.Lys1123Gln	missense_variant	17/27	5	NM_001330260.2	ENSP00000487583	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 28, 2022

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. 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: 530412). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1123 of the SCN8A protein (p.Lys1123Gln). -

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

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jul 16, 2021

The inherited c.3367A>C (p.Lys1123Gln) variant identified in the SCN8A gene substitutes a very well conserved Lysine for Glutamine at amino acid 1123/1981 (exon 17/27). This variant is absent from gnomAD(v3.1.1), suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.013) and Pathogenic (REVEL; score:0.6389) to the function of the canonical transcript.This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:530412) and to our current knowledge has not been reported in affected individuals in the literature. The p.Lys1123 residue is within one of the cytoplasmic domains of SCN8A (UniProtKB:Q9UQD0). Given the lack of compelling evidence for its pathogenicity, the inherited c.3367A>C (p.Lys1123Gln) variant identified in the SCN8A gene is reported as a Variant of UncertainSignificance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;.;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T;.;T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.53	D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.1	M;M;M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.9	D;D;D;.;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.013	D;D;D;.;.
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		1.0	D;.;.;.;.
Vest4		0.52
MutPred		0.44		Loss of ubiquitination at K1123 (P = 0.0047);Loss of ubiquitination at K1123 (P = 0.0047);Loss of ubiquitination at K1123 (P = 0.0047);.;Loss of ubiquitination at K1123 (P = 0.0047);
MVP		0.93
MPC		2.3
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.34
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1555226186; hg19: chr12-52163114;