rs1555218603

Positions:

• chr12-51699570-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_014191.4(SCN8A):​c.707G>A​(p.Gly236Asp) variant causes a missense, splice region 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. 14/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN8A NM_014191.4 missense, splice_region
• Scores: Splicing: ADA: 0.9991
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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 Uncertain_significance. Variant got 4 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.707G>A	p.Gly236Asp	missense_variant, splice_region_variant	7/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.707G>A	p.Gly236Asp	missense_variant, splice_region_variant	7/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.707G>A	p.Gly236Asp	missense_variant, splice_region_variant	7/26		NP_001171455.1
SCN8A	NM_001369788.1	c.707G>A	p.Gly236Asp	missense_variant, splice_region_variant	7/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.707G>A	p.Gly236Asp	missense_variant, splice_region_variant	7/27	1	NM_014191.4	ENSP00000346534	P4
SCN8A	ENST00000627620.5	c.707G>A	p.Gly236Asp	missense_variant, splice_region_variant	7/27	5	NM_001330260.2	ENSP00000487583	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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

Aug 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;D;.;.;.;.;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;.;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	.;H;H;H;H;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-6.7	.;D;D;D;.;.;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	.;D;D;D;.;.;.
Sift4G	Pathogenic	0.0010	.;D;D;D;D;D;D
Polyphen		0.82, 1.0	.;P;.;.;D;.;.
Vest4		0.83, 0.88, 0.88, 0.90, 0.89
MutPred		0.67		Loss of MoRF binding (P = 0.0817);Loss of MoRF binding (P = 0.0817);Loss of MoRF binding (P = 0.0817);Loss of MoRF binding (P = 0.0817);Loss of MoRF binding (P = 0.0817);Loss of MoRF binding (P = 0.0817);.;
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.96
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.84
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: rs1555218603; hg19: chr12-52093354;