rs796053216

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS1PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_001330260.2(SCN8A):c.4423G>A(p.Gly1475Arg) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1475A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SCN8A
NM_001330260.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 10.0

Publications

19 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 21 ACMG points.

PS1

Transcript NM_001330260.2 (SCN8A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM1

In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001330260.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-51790402-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3635206.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the SCN8A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 213 curated pathogenic missense variants (we use a threshold of 10). The gene has 45 curated benign missense variants. Gene score misZ: 0.78755 (below the threshold of 3.09). Trascript score misZ: 10.436 (above the threshold of 3.09). GenCC associations: The gene is linked to myoclonus, familial, 2, developmental and epileptic encephalopathy, 13, undetermined early-onset epileptic encephalopathy, benign familial infantile epilepsy, complex neurodevelopmental disorder, seizures, benign familial infantile, 5, cognitive impairment with or without cerebellar ataxia, infantile convulsions and choreoathetosis.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 12-51790401-G-A is Pathogenic according to our data. Variant chr12-51790401-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 207119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2 link	c.4423G>A	p.Gly1475Arg	missense_variant	Exon 25 of 27	ENST00000627620.5	NP_001317189.1	Q9UQD0-2Q6B4S4
SCN8A	NM_014191.4 link	c.4423G>A	p.Gly1475Arg	missense_variant	Exon 25 of 27	ENST00000354534.11	NP_055006.1	Q9UQD0-1
SCN8A	NM_001177984.3 link	c.4300G>A	p.Gly1434Arg	missense_variant	Exon 24 of 26		NP_001171455.1	Q9UQD0-5
SCN8A	NM_001369788.1 link	c.4300G>A	p.Gly1434Arg	missense_variant	Exon 24 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN8A	ENST00000354534.11 link	c.4423G>A	p.Gly1475Arg	missense_variant	Exon 25 of 27	1	NM_014191.4	ENSP00000346534.4	Q9UQD0-1
SCN8A	ENST00000627620.5 link	c.4423G>A	p.Gly1475Arg	missense_variant	Exon 25 of 27	5	NM_001330260.2	ENSP00000487583.2	Q9UQD0-2
SCN8A	ENST00000599343.5 link	c.4456G>A	p.Gly1486Arg	missense_variant	Exon 24 of 26	5		ENSP00000476447.3	Q9UQD0-3
SCN8A	ENST00000355133.7 link	c.4300G>A	p.Gly1434Arg	missense_variant	Exon 23 of 25	1		ENSP00000347255.4	Q9UQD0-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1451118

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721744

African (AFR)

AF:

0.00

AC:

AN:

32938

American (AMR)

AF:

0.00

AC:

AN:

42604

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25910

East Asian (EAS)

AF:

0.00

AC:

AN:

39366

South Asian (SAS)

AF:

0.00

AC:

AN:

84268

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53304

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107004

Other (OTH)

AF:

0.00

AC:

AN:

59990

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SCN8A: PM1, PM2, PS4:Moderate, PP2, PP3, PP4, PS3:Supporting -

May 19, 2020

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29235621, 30776697, 27864847, 29128679, 28923014, 29429461, 30171078, 30615093, 31402610, 32090326, 32040247) -

Developmental and epileptic encephalopathy, 13

Pathogenic:2

Jan 03, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

he variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000207119, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.75, 3CNET: 0.972, PP3_P). A missense variant is a common mechanism associated with Developmental and epileptic encephalopathy 13 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). TTherefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Oct 29, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy

Pathogenic:1

Nov 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1475 of the SCN8A protein (p.Gly1475Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 27864847, 28923014, 30171078). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207119). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN8A protein function. Experimental studies have shown that this missense change affects SCN8A function (PMID: 30615093). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Epileptic encephalopathy

Pathogenic:1

Nov 16, 2016

Neurogenetics Laboratory - MEYER, AOU Meyer

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Epilepsy

Pathogenic:1

Nov 06, 2017

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was identified in a mosaic state in a young female patient with epilepsy. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;.;.;.;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;T;.;D;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.85

D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.8

M;.;.;.;M

PhyloP100

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-6.4

D;D;D;.;.

REVEL

Pathogenic

0.75

Sift

Benign

0.051

T;T;D;.;.

Sift4G

Uncertain

0.060

T;T;T;T;T

Polyphen

0.74

P;.;.;.;.

Vest4

0.89

MutPred

0.39

Gain of catalytic residue at G1475 (P = 0.0387);.;.;.;Gain of catalytic residue at G1475 (P = 0.0387);

MVP

0.93

MPC

1.5

ClinPred

0.99

GERP RS

4.7

Varity_R

0.39

gMVP

0.92

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

1.0

Position offset: 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