chr12-51769943-C-T

Position:

• chr12-51769943-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_014191.4(SCN8A):​c.3448C>T​(p.Gln1150Ter) 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: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN8A NM_014191.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.89

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 12 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 12-51769943-C-T is Pathogenic according to our data. Variant chr12-51769943-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 522036.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.3448C>T	p.Gln1150Ter	stop_gained	18/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.3448C>T	p.Gln1150Ter	stop_gained	18/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.3448C>T	p.Gln1150Ter	stop_gained	18/26		NP_001171455.1
SCN8A	NM_001369788.1	c.3448C>T	p.Gln1150Ter	stop_gained	18/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.3448C>T	p.Gln1150Ter	stop_gained	18/27	1	NM_014191.4	ENSP00000346534	P4
SCN8A	ENST00000627620.5	c.3448C>T	p.Gln1150Ter	stop_gained	18/27	5	NM_001330260.2	ENSP00000487583	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1454790 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 722648

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2023

The c.3448C>T (p.Q1150*) alteration, located in exon 18 (coding exon 17) of the SCN8A gene, consists of a C to T substitution at nucleotide position 3448. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 1150. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. for SCN8A-related neurodevelopmental disorder; however, its clinical significance for SCN8A-related seizure disorder 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Benign	0.33	N
MutationTaster	Benign	1.0	A;A
Vest4		0.79
GERP RS		5.1

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: rs1555226280; hg19: chr12-52163727;