chr12-51662866-TTCACCC-T

Position:

• chr12-51662866-TTCACCC-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4 PP3

The NM_014191.4(SCN8A):​c.50_55del​(p.Phe17_Pro19delinsSer) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN8A NM_014191.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.02

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_014191.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.50_55del	p.Phe17_Pro19delinsSer	inframe_deletion	2/27	ENST00000627620.5
SCN8A	NM_014191.4	c.50_55del	p.Phe17_Pro19delinsSer	inframe_deletion	2/27	ENST00000354534.11
SCN8A	NM_001177984.3	c.50_55del	p.Phe17_Pro19delinsSer	inframe_deletion	2/26
SCN8A	NM_001369788.1	c.50_55del	p.Phe17_Pro19delinsSer	inframe_deletion	2/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.50_55del	p.Phe17_Pro19delinsSer	inframe_deletion	2/27	1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.50_55del	p.Phe17_Pro19delinsSer	inframe_deletion	2/27	5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

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

Oct 09, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with SCN8A-related conditions. This variant is not present in population databases (ExAC no frequency). This variant, c.50_55del, is a complex sequence change that results in the deletion of 3 and insertion of 1 amino acid(s) in the SCN8A protein (p.Phe17_Pro19delinsSer). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 01, 2022

Reported as a variant of uncertain significance in a patient with early infantile epileptic encephalopathy in the ClinVar database (Wong et al., 2021; ClinVar); In-frame deletion of three amino acids and insertion of one amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34867351) -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr12-52056650;