rs1555229543

Variant names:

• chr12-51794600-G-A
• rs1555229543
• NM_001330260.2:c.4754G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001330260.2(SCN8A):​c.4754G>A​(p.Trp1585*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN8A NM_001330260.2 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P: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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-51794600-G-A is Pathogenic according to our data. Variant chr12-51794600-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521907.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.4754G>A	p.Trp1585*	stop_gained	Exon 26 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.4754G>A	p.Trp1585*	stop_gained	Exon 26 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.4631G>A	p.Trp1544*	stop_gained	Exon 25 of 26		NP_001171455.1
SCN8A	NM_001369788.1	c.4631G>A	p.Trp1544*	stop_gained	Exon 25 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.4754G>A	p.Trp1585*	stop_gained	Exon 26 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.4754G>A	p.Trp1585*	stop_gained	Exon 26 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.4787G>A	p.Trp1596*	stop_gained	Exon 25 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.4631G>A	p.Trp1544*	stop_gained	Exon 24 of 25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461694 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727128

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Oct 13, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4754G>A (p.W1585*) alteration, located in exon 26 (coding exon 25) of the SCN8A gene, consists of a G to A substitution at nucleotide position 4754. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 1585. This alteration occurs at the 3' terminus of the SCN8A gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 20% of the protein. However, premature stop codons are typically deleterious in nature, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). _x000D_ _x000D_ 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 likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	48
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.92
GERP RS		4.9

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: rs1555229543; hg19: chr12-52188384;