rs1352024223

Positions:

• chr12-51721871-GC-G
• chr12-51721871-GC-GCC

Variant summary

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

The NM_014191.4(SCN8A):​c.1965del​(p.Gly656AlafsTer27) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,782 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SCN8A NM_014191.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.00400

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 12-51721871-GC-G is Pathogenic according to our data. Variant chr12-51721871-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 530450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.1965del	p.Gly656AlafsTer27	frameshift_variant	12/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.1965del	p.Gly656AlafsTer27	frameshift_variant	12/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.1965del	p.Gly656AlafsTer27	frameshift_variant	12/26		NP_001171455.1
SCN8A	NM_001369788.1	c.1965del	p.Gly656AlafsTer27	frameshift_variant	12/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.1965del	p.Gly656AlafsTer27	frameshift_variant	12/27	1	NM_014191.4	ENSP00000346534	P4
SCN8A	ENST00000627620.5	c.1965del	p.Gly656AlafsTer27	frameshift_variant	12/27	5	NM_001330260.2	ENSP00000487583	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449782 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721678

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000240

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2023

The c.1965delC (p.G656Afs*27) alteration, located in exon 12 (coding exon 11) of the SCN8A gene, consists of a deletion of one nucleotide at position 1965, causing a translational frameshift with a predicted alternate stop codon after 27 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay._x000D_ _x000D_ Based on the available evidence, the SCN8A c.1965delC (p.G656Afs*27) alteration is classified as pathogenic for SCN8A-related neurodevelopmental disorder; however, its clinical significance for SCN8A-related seizure disorders is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 12, 2021

This sequence change creates a premature translational stop signal (p.Gly656Alafs*27) 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. ClinVar contains an entry for this variant (Variation ID: 530450). For these reasons, this variant has been classified as Pathogenic. -

SCN8A-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Variantyx, Inc.

Nov 07, 2022

This is a frameshift variant in the SCN8A gene (OMIM 600702). Heterozygous pathogenic variants in this gene are associated with SCN8A-related disorders. This variant introduces a premature termination codon in exon 12 out of 27. It is expected to result in loss of function, which is a known disease mechanism for SCN8A (PMID: 28702509, 34431999) (PVS1). This variant is absent from control populations (https://gnomad.broadinstitute.org/) (PM2_Supporting). This variant has not been reported previously in the medical literature. Based on the current evidence, this variant is classified as likely pathogenic for SCN8A-related disorders. -

Computational scores

Source: dbNSFP v4.3

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: rs1352024223; hg19: chr12-52115655;