rs1352024223

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001330260.2(SCN8A):c.1965delC(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 (★★). Synonymous variant affecting the same amino acid position (i.e. P655P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SCN8A
NM_001330260.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 0.00400

Publications

0 publications found

Variant links:

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

SCN8A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 530450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SCN8A	NM_001330260.2 link	c.1965delC	p.Gly656AlafsTer27	frameshift_variant	Exon 12 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4 link	c.1965delC	p.Gly656AlafsTer27	frameshift_variant	Exon 12 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3 link	c.1965delC	p.Gly656AlafsTer27	frameshift_variant	Exon 12 of 26		NP_001171455.1
SCN8A	NM_001369788.1 link	c.1965delC	p.Gly656AlafsTer27	frameshift_variant	Exon 12 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SCN8A	ENST00000354534.11 link	c.1965delC	p.Gly656AlafsTer27	frameshift_variant	Exon 12 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5 link	c.1965delC	p.Gly656AlafsTer27	frameshift_variant	Exon 12 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5 link	c.1965delC	p.Gly656AlafsTer12	frameshift_variant	Exon 11 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7 link	c.1965delC	p.Gly656AlafsTer27	frameshift_variant	Exon 11 of 25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1449782

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721678

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000240

AC:

AN:

41668

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111774

Other (OTH)

AF:

0.00

AC:

AN:

60292

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Oct 13, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Developmental and epileptic encephalopathy

Pathogenic:1

Nov 12, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 530450). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. This variant is not present in population databases (gnomAD no frequency). 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). -

SCN8A-related disorder

Pathogenic:1

Nov 07, 2022

Variantyx, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0040

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over