12-51790401-G-C

Position:

• chr12-51790401-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001330260.2(SCN8A):​c.4423G>C​(p.Gly1475Arg) 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: 33)
• Consequence: SCN8A NM_001330260.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• 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 Likely_pathogenic. Variant got 7 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 10.436 (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, 0.854
• PP5: Variant 12-51790401-G-C is Pathogenic according to our data. Variant chr12-51790401-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1345807.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.4423G>C	p.Gly1475Arg	missense_variant	25/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.4423G>C	p.Gly1475Arg	missense_variant	25/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.4300G>C	p.Gly1434Arg	missense_variant	24/26		NP_001171455.1
SCN8A	NM_001369788.1	c.4300G>C	p.Gly1434Arg	missense_variant	24/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.4423G>C	p.Gly1475Arg	missense_variant	25/27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.4423G>C	p.Gly1475Arg	missense_variant	25/27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.4456G>C	p.Gly1486Arg	missense_variant	24/26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.4300G>C	p.Gly1434Arg	missense_variant	23/25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

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

Feb 05, 2022

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: "Benign"; Align-GVGD: "Class C0"). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1475 of the SCN8A protein (p.Gly1475Arg). This variant is not present in population databases (gnomAD no frequency). A different variant (c.4423G>A) giving rise to the same protein effect has been determined to be pathogenic (PMID: 27864847, 28923014, 30171078, 30615093). This suggests that this variant is also likely to be causative of disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;T;.;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.8	M;.;.;.;M
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.4	D;D;D;.;.
REVEL	Pathogenic	0.78
Sift	Benign	0.051	T;T;D;.;.
Sift4G	Uncertain	0.060	T;T;T;T;T
Polyphen		0.56	P;.;.;.;.
Vest4		0.89
MutPred		0.39		Gain of catalytic residue at G1475 (P = 0.0387);.;.;.;Gain of catalytic residue at G1475 (P = 0.0387);
MVP		0.93
MPC		1.5
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.39
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 4
DS_AL_spliceai		0.30		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-52184185;