NM_001330260.2:c.4748T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 3P and 10B. PM1PP2BP4BP6BS1BS2

The NM_001330260.2(SCN8A):c.4748T>C(p.Ile1583Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000467 in 1,613,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1583V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00049 ( 0 hom. )

Consequence

SCN8A
NM_001330260.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8O:1

Conservation

PhyloP100: 5.09

Publications

10 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: Benign. The variant received -7 ACMG points.

PM1

In a repeat IV (size 297) in uniprot entity SCN8A_HUMAN there are 71 pathogenic changes around while only 13 benign (85%) in NM_001330260.2

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.41254112).

BP6

Variant 12-51794594-T-C is Benign according to our data. Variant chr12-51794594-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 130248. Variant chr12-51794594-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 130248. Variant chr12-51794594-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 130248. Variant chr12-51794594-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 130248. Variant chr12-51794594-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 130248. Variant chr12-51794594-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 130248. Variant chr12-51794594-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 130248. Variant chr12-51794594-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 130248. Variant chr12-51794594-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 130248. Variant chr12-51794594-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 130248. Variant chr12-51794594-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 130248.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000256 (39/152196) while in subpopulation NFE AF = 0.000485 (33/68026). AF 95% confidence interval is 0.000355. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2 link	c.4748T>C	p.Ile1583Thr	missense_variant	Exon 26 of 27	ENST00000627620.5	NP_001317189.1	Q9UQD0-2Q6B4S4
SCN8A	NM_014191.4 link	c.4748T>C	p.Ile1583Thr	missense_variant	Exon 26 of 27	ENST00000354534.11	NP_055006.1	Q9UQD0-1
SCN8A	NM_001177984.3 link	c.4625T>C	p.Ile1542Thr	missense_variant	Exon 25 of 26		NP_001171455.1	Q9UQD0-5
SCN8A	NM_001369788.1 link	c.4625T>C	p.Ile1542Thr	missense_variant	Exon 25 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN8A	ENST00000354534.11 link	c.4748T>C	p.Ile1583Thr	missense_variant	Exon 26 of 27	1	NM_014191.4	ENSP00000346534.4	Q9UQD0-1
SCN8A	ENST00000627620.5 link	c.4748T>C	p.Ile1583Thr	missense_variant	Exon 26 of 27	5	NM_001330260.2	ENSP00000487583.2	Q9UQD0-2
SCN8A	ENST00000599343.5 link	c.4781T>C	p.Ile1594Thr	missense_variant	Exon 25 of 26	5		ENSP00000476447.3	Q9UQD0-3
SCN8A	ENST00000355133.7 link	c.4625T>C	p.Ile1542Thr	missense_variant	Exon 24 of 25	1		ENSP00000347255.4	Q9UQD0-5

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000205

AC:

AN:

249166

AF XY:

0.000185

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 FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.000398

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000488

AC:

714

AN:

1461704

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

342

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000617

AC:

686

AN:

1111864

Other (OTH)

AF:

0.000315

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

103

138

172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000256

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41446

American (AMR)

AF:

0.0000654

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000485

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000424

Hom.:

Bravo

AF:

0.000268

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000241

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Mar 19, 2021

GeneDx

Significance:Likely benign

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); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32090326, 26220391, 33083721) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SCN8A: PP2, BS2 -

Jan 02, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 24, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SCN8A c.4748T>C (p.Ile1583Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 249166 control chromosomes, predominantly at a frequency of 0.0004 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in SCN8A causing Early Infantile Epileptic Encephalopathy 13, allowing no conclusion about variant significance. c.4748T>C has been reported in the literature in two individuals affected with epilepsy (Brunklaus_2020, Dong_2020), without strong evidence for causality . These report(s) do not provide unequivocal conclusions about association of the variant with Early Infantile Epileptic Encephalopathy 13. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 130248). Based on the evidence outlined above, the variant was classified as likely benign. -

Inborn genetic diseases

Benign:1

Feb 09, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Developmental and epileptic encephalopathy

Benign:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 13

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

0.0060

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

(source)

DANN

Benign

0.34

DEOGEN2

Uncertain

0.79

D;.;.;.;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.78

T;T;.;T;T

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.41

T;T;T;T;T

MetaSVM

Pathogenic

0.97

MutationAssessor

Benign

1.9

L;.;.;.;L

PhyloP100

5.1

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.0

D;D;D;.;.

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0040

D;D;D;.;.

Sift4G

Benign

0.66

T;T;T;T;T

Polyphen

0.90

P;.;.;.;.

Vest4

0.54

MVP

0.80

MPC

1.8

ClinPred

0.19

GERP RS

4.9

Varity_R

0.48

gMVP

0.84

Mutation Taster

=81/19

polymorphism

(source)

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over