rs397514738

Positions:

• chr12-51786590-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_014191.4(SCN8A):​c.3991C>G​(p.Leu1331Val) variant causes a missense change involving the alteration of a non-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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN8A NM_014191.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:2
• Conservation: PhyloP100: 1.33

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 10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain 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, 0.956
• PP5: Variant 12-51786590-C-G is Pathogenic according to our data. Variant chr12-51786590-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 60709.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-51786590-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.3991C>G	p.Leu1331Val	missense_variant	22/27	ENST00000627620.5
SCN8A	NM_014191.4	c.3991C>G	p.Leu1331Val	missense_variant	22/27	ENST00000354534.11
SCN8A	NM_001177984.3	c.3868C>G	p.Leu1290Val	missense_variant	21/26
SCN8A	NM_001369788.1	c.3868C>G	p.Leu1290Val	missense_variant	21/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.3991C>G	p.Leu1331Val	missense_variant	22/27	1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.3991C>G	p.Leu1331Val	missense_variant	22/27	5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:2

Revision: no assertion criteria provided

Submissions by phenotype

Developmental and epileptic encephalopathy, 13 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2013	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Complex neurodevelopmental disorder Other:1

not provided, no classification provided

literature only

Channelopathy-Associated Epilepsy Research Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D;.;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;.;.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.8	D;D;D;.;.
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;D;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		0.99	D;.;.;.;.
Vest4		0.68
MutPred		0.87		Gain of catalytic residue at L1331 (P = 0.1218);.;.;.;Gain of catalytic residue at L1331 (P = 0.1218);
MVP		0.98
MPC		1.9
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.77
gMVP		0.98

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: rs397514738; hg19: chr12-52180374;