rs758891499

Positions:

chr12-51662825-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BS1_SupportingBS2

The ENST00000354534.11(SCN8A):c.8C>T(p.Ala3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,542 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A3A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

SCN8A
ENST00000354534.11 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.15

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 -5 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 10.278 (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.

BP4

Computational evidence support a benign effect (MetaRNN=0.3019017).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000137 (20/1461366) while in subpopulation MID AF= 0.000694 (4/5764). AF 95% confidence interval is 0.000236. There are 0 homozygotes in gnomad4_exome. There are 9 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SCN8A	NM_001330260.2 linkuse as main transcript	c.8C>T	p.Ala3Val	missense_variant	2/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4 linkuse as main transcript	c.8C>T	p.Ala3Val	missense_variant	2/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3 linkuse as main transcript	c.8C>T	p.Ala3Val	missense_variant	2/26		NP_001171455.1
SCN8A	NM_001369788.1 linkuse as main transcript	c.8C>T	p.Ala3Val	missense_variant	2/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11 linkuse as main transcript	c.8C>T	p.Ala3Val	missense_variant	2/27	1	NM_014191.4	ENSP00000346534	P4	Q9UQD0-1
SCN8A	ENST00000627620.5 linkuse as main transcript	c.8C>T	p.Ala3Val	missense_variant	2/27	5	NM_001330260.2	ENSP00000487583	A1	Q9UQD0-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000203

AC:

AN:

246654

Hom.:

AF XY:

0.0000224

AC XY:

AN XY:

134092

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:

0.0000270

Gnomad OTH exome

AF:

0.000334

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461366

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726944

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2017

The p.A3V variant (also known as c.8C>T), located in coding exon 1 of the SCN8A gene, results from a C to T substitution at nucleotide position 8. The alanine at codon 3 is replaced by valine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Early infantile epileptic encephalopathy with suppression bursts

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3 of the SCN8A protein (p.Ala3Val). This variant is present in population databases (rs758891499, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. ClinVar contains an entry for this variant (Variation ID: 461351). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Uncertain

0.094

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.52

.;D;.;.;.;.

Eigen

Benign

0.14

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.95

D;D;D;.;D;D

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.30

T;T;T;T;T;T

MetaSVM

Uncertain

0.55

MutationAssessor

Uncertain

2.2

.;M;M;M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.0

.;N;N;N;.;.

REVEL

Uncertain

0.47

Sift

Benign

0.071

.;T;T;T;.;.

Sift4G

Uncertain

0.024

.;D;D;D;D;D

Polyphen

0.84

.;P;.;.;.;.

Vest4

0.35, 0.37, 0.38, 0.37, 0.39

MutPred

0.23

Loss of methylation at R4 (P = 0.0806);Loss of methylation at R4 (P = 0.0806);Loss of methylation at R4 (P = 0.0806);Loss of methylation at R4 (P = 0.0806);Loss of methylation at R4 (P = 0.0806);Loss of methylation at R4 (P = 0.0806);

MVP

0.89

MPC

1.2

ClinPred

0.49

GERP RS

4.1

Varity_R

0.16

gMVP

0.69

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