rs761386688

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2

The NM_001330260.2(SCN8A):c.3267C>A(p.Asn1089Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,698 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000089 ( 1 hom. )

Consequence

SCN8A
NM_001330260.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: 0.556

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 links:

SCN8A (HGNC:):

SCN8A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN8A. . Gene score misZ 0.78755 (greater than the threshold 3.09). Trascript score misZ 10.436 (greater than threshold 3.09). GenCC has associacion of gene with myoclonus, familial, 2, infantile convulsions and choreoathetosis, cognitive impairment with or without cerebellar ataxia, undetermined early-onset epileptic encephalopathy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 13, benign familial infantile epilepsy, seizures, benign familial infantile, 5.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.779

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2 linkuse as main transcript	c.3267C>A	p.Asn1089Lys	missense_variant	17/27	ENST00000627620.5	NP_001317189.1	Q9UQD0-2Q6B4S4
SCN8A	NM_014191.4 linkuse as main transcript	c.3267C>A	p.Asn1089Lys	missense_variant	17/27	ENST00000354534.11	NP_055006.1	Q9UQD0-1
SCN8A	NM_001177984.3 linkuse as main transcript	c.3267C>A	p.Asn1089Lys	missense_variant	17/26		NP_001171455.1	Q9UQD0-5
SCN8A	NM_001369788.1 linkuse as main transcript	c.3267C>A	p.Asn1089Lys	missense_variant	17/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN8A	ENST00000354534.11 linkuse as main transcript	c.3267C>A	p.Asn1089Lys	missense_variant	17/27	1	NM_014191.4	ENSP00000346534.4	Q9UQD0-1
SCN8A	ENST00000627620.5 linkuse as main transcript	c.3267C>A	p.Asn1089Lys	missense_variant	17/27	5	NM_001330260.2	ENSP00000487583.2	Q9UQD0-2
SCN8A	ENST00000599343.5 linkuse as main transcript	c.3300C>A	p.Asn1100Lys	missense_variant	16/26	5		ENSP00000476447.3	Q9UQD0-3
SCN8A	ENST00000355133.7 linkuse as main transcript	c.3267C>A	p.Asn1089Lys	missense_variant	16/25	1		ENSP00000347255.4	Q9UQD0-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250118

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135318

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461698

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727130

show subpopulations

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:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 13

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 03, 2017

- -

Early infantile epileptic encephalopathy with suppression bursts

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 27, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SCN8A protein function. ClinVar contains an entry for this variant (Variation ID: 522699). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. This variant is present in population databases (rs761386688, gnomAD 0.003%). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1089 of the SCN8A protein (p.Asn1089Lys). -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Apr 18, 2023

ACMG categories: PM2 -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Benign

-0.030

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

D;.;.;.;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.92

D;D;.;D;D

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.78

D;D;D;D;D

MetaSVM

Uncertain

0.44

MutationAssessor

Pathogenic

3.0

M;M;M;.;M

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.4

D;D;D;.;.

REVEL

Uncertain

0.56

Sift

Uncertain

0.0010

D;D;D;.;.

Sift4G

Benign

0.096

T;T;T;T;T

Polyphen

0.99

D;.;.;.;.

Vest4

0.81

MutPred

0.60

Gain of methylation at N1089 (P = 0.0085);Gain of methylation at N1089 (P = 0.0085);Gain of methylation at N1089 (P = 0.0085);.;Gain of methylation at N1089 (P = 0.0085);

MVP

0.85

MPC

2.0

ClinPred

0.97

GERP RS

-4.1

Varity_R

0.90

gMVP

0.84

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over