12-51745907-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_001330260.2(SCN8A):c.2003C>T(p.Thr668Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000254 in 1,575,754 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T668A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

SCN8A
NM_001330260.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2O:1

Conservation

PhyloP100: 5.84

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

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, 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.

BS2

High AC in GnomAdExome4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2 link	c.2003C>T	p.Thr668Ile	missense_variant	Exon 13 of 27	ENST00000627620.5	NP_001317189.1	Q9UQD0-2Q6B4S4
SCN8A	NM_014191.4 link	c.2003C>T	p.Thr668Ile	missense_variant	Exon 13 of 27	ENST00000354534.11	NP_055006.1	Q9UQD0-1
SCN8A	NM_001177984.3 link	c.2003C>T	p.Thr668Ile	missense_variant	Exon 13 of 26		NP_001171455.1	Q9UQD0-5
SCN8A	NM_001369788.1 link	c.2003C>T	p.Thr668Ile	missense_variant	Exon 13 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN8A	ENST00000354534.11 link	c.2003C>T	p.Thr668Ile	missense_variant	Exon 13 of 27	1	NM_014191.4	ENSP00000346534.4	Q9UQD0-1
SCN8A	ENST00000627620.5 link	c.2003C>T	p.Thr668Ile	missense_variant	Exon 13 of 27	5	NM_001330260.2	ENSP00000487583.2	Q9UQD0-2
SCN8A	ENST00000599343.5 link	c.2036C>T	p.Thr679Ile	missense_variant	Exon 12 of 26	5		ENSP00000476447.3	Q9UQD0-3
SCN8A	ENST00000355133.7 link	c.2003C>T	p.Thr668Ile	missense_variant	Exon 12 of 25	1		ENSP00000347255.4	Q9UQD0-5

Frequencies

GnomAD3 genomes

AF:

0.00000664

AC:

AN:

150584

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000245

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000137

AC:

AN:

218480

Hom.:

AF XY:

0.00000843

AC XY:

AN XY:

118636

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000292

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1425170

Hom.:

Cov.:

AF XY:

0.0000198

AC XY:

AN XY:

707702

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000355

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000664

AC:

AN:

150584

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73366

show subpopulations

Gnomad4 AFR

AF:

0.0000245

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 01, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SCN8A c.2003C>T (p.Thr668Ile) results in a non-conservative amino acid change located in the Voltage-gated Na+ ion channel, cytoplasmic domain (IPR024583) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 218480 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2003C>T has been reported in the literature in at-least one individual affected neuropsychiatric disorder (Li_2016). 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. The following publication has been ascertained in the context of this evaluation (PMID: 25849321). ClinVar contains an entry for this variant (Variation ID: 253283). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Early infantile epileptic encephalopathy with suppression bursts

Uncertain:1

Oct 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 668 of the SCN8A protein (p.Thr668Ile). This variant is present in population databases (rs758253791, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of SCN8A-related conditions (PMID: 25849321; Invitae). ClinVar contains an entry for this variant (Variation ID: 253283). 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. 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. -

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

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.73

D;.;.;.;.;.

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.84

T;T;.;T;T;T

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.72

D;D;D;D;D;D

MetaSVM

Pathogenic

0.80

MutationAssessor

Uncertain

2.1

M;M;M;.;M;.

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.8

D;D;D;.;.;.

REVEL

Pathogenic

0.72

Sift

Benign

0.030

D;D;D;.;.;.

Sift4G

Benign

0.18

T;T;T;T;T;D

Polyphen

0.74

P;.;.;P;.;.

Vest4

0.44

MutPred

0.35

Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);.;Gain of loop (P = 0.0166);.;

MVP

0.89

MPC

1.1

ClinPred

0.73

GERP RS

5.2

Varity_R

0.36

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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