12-51790425-G-T

Variant names:

• chr12-51790425-G-T
• rs879255652
• NM_001330260.2:c.4447G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001330260.2(SCN8A):​c.4447G>T​(p.Glu1483*) variant causes a stop gained 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN8A NM_001330260.2 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 21 publications found

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]

SCN8A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 13

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• cognitive impairment with or without cerebellar ataxia

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• seizures, benign familial infantile, 5

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile convulsions and choreoathetosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myoclonus, familial, 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.4447G>T	p.Glu1483*	stop_gained	Exon 25 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.4447G>T	p.Glu1483*	stop_gained	Exon 25 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.4324G>T	p.Glu1442*	stop_gained	Exon 24 of 26		NP_001171455.1
SCN8A	NM_001369788.1	c.4324G>T	p.Glu1442*	stop_gained	Exon 24 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.4447G>T	p.Glu1483*	stop_gained	Exon 25 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.4447G>T	p.Glu1483*	stop_gained	Exon 25 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.4480G>T	p.Glu1494*	stop_gained	Exon 24 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.4324G>T	p.Glu1442*	stop_gained	Exon 23 of 25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.000563 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	49
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		10
Vest4		0.77
GERP RS		4.7
Mutation Taster		=1/199	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs879255652; hg19: chr12-52184209;