rs1555218657

Variant names:

• chr12-51699695-C-T
• rs1555218657
• NM_001330260.2:c.832C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001330260.2(SCN8A):​c.832C>T​(p.Arg278*) variant causes a stop gained 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN8A NM_001330260.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.38

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-51699695-C-T is Pathogenic according to our data. Variant chr12-51699695-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 461350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.832C>T	p.Arg278*	stop_gained	Exon 7 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.832C>T	p.Arg278*	stop_gained	Exon 7 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.832C>T	p.Arg278*	stop_gained	Exon 7 of 26		NP_001171455.1
SCN8A	NM_001369788.1	c.832C>T	p.Arg278*	stop_gained	Exon 7 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.832C>T	p.Arg278*	stop_gained	Exon 7 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.832C>T	p.Arg278*	stop_gained	Exon 7 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.832C>T	p.Arg278*	stop_gained	Exon 6 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.832C>T	p.Arg278*	stop_gained	Exon 6 of 25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Aug 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 461350). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. This sequence change creates a premature translational stop signal (p.Arg278*) in the SCN8A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN8A are known to be pathogenic (PMID: 19254928, 32651551). -

not provided Pathogenic:1

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN8A: PVS1, PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.92	D
Vest4		0.87, 0.88, 0.88, 0.88
GERP RS		3.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1555218657; hg19: chr12-52093479; COSMIC: COSV61978882;