rs751979396

Positions:

chr12-51794533-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1BS2

This summary comes from the ClinGen Evidence Repository: The c.4687A>G variant in SCN8A is a missense variant predicted to cause the substitution of isoleucine by valine at amino acid 1563 (p.Ile1563Val). The variant is present at a frequency of 0.000008674 (14 alleles) of the total population in gnomAD v4.0, which exceeds the threshold for BS1. Additionally, the variant was identified in 7 unaffected adults who were referred for clinical testing as part as trio exome analysis (internal data, GeneDx, July 2023). It was identified as homozygous in an individual undergoing trio exome sequencing for an unrelated condition, without a neurodevelopmental disorder, in which both parents were heterozygous and unaffected (BS2, GeneDx internal data, July 2023). In summary, this variant meets the criteria for BENIGN for Autosomal Dominant Complex Neurodevelopmental Disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP (Version 1.0, approved 7/25/23): BS1, BS2 LINK:https://erepo.genome.network/evrepo/ui/classification/CA6571849/MONDO:0100038/070

Frequency

Genomes: 𝑓 0.000013 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

SCN8A
ENST00000354534.11 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:2

Conservation

PhyloP100: 1.89

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 Benign. Variant got -8 ACMG points.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SCN8A	NM_001330260.2 linkuse as main transcript	c.4687A>G	p.Ile1563Val	missense_variant	26/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4 linkuse as main transcript	c.4687A>G	p.Ile1563Val	missense_variant	26/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3 linkuse as main transcript	c.4564A>G	p.Ile1522Val	missense_variant	25/26		NP_001171455.1
SCN8A	NM_001369788.1 linkuse as main transcript	c.4564A>G	p.Ile1522Val	missense_variant	25/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11 linkuse as main transcript	c.4687A>G	p.Ile1563Val	missense_variant	26/27	1	NM_014191.4	ENSP00000346534	P4	Q9UQD0-1
SCN8A	ENST00000627620.5 linkuse as main transcript	c.4687A>G	p.Ile1563Val	missense_variant	26/27	5	NM_001330260.2	ENSP00000487583	A1	Q9UQD0-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

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:

0.00000803

AC:

AN:

249196

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135198

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:

0.00000885

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461710

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000487

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 23, 2021	- -

Early infantile epileptic encephalopathy with suppression bursts

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1563 of the SCN8A protein (p.Ile1563Val). This variant is present in population databases (rs751979396, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of SCN8A-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 568706). 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 with a negative predictive value of 95%. 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. -

Complex neurodevelopmental disorder

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel, Clingen

May 09, 2024

The c.4687A>G variant in SCN8A is a missense variant predicted to cause the substitution of isoleucine by valine at amino acid 1563 (p.Ile1563Val). The variant is present at a frequency of 0.000008674 (14 alleles) of the total population in gnomAD v4.0, which exceeds the threshold for BS1. Additionally, the variant was identified in 7 unaffected adults who were referred for clinical testing as part as trio exome analysis (internal data, GeneDx, July 2023). It was identified as homozygous in an individual undergoing trio exome sequencing for an unrelated condition, without a neurodevelopmental disorder, in which both parents were heterozygous and unaffected (BS2, GeneDx internal data, July 2023). In summary, this variant meets the criteria for BENIGN for Autosomal Dominant Complex Neurodevelopmental Disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP (Version 1.0, approved 7/25/23): BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Uncertain

0.049

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Benign

0.25

DEOGEN2

Uncertain

0.57

D;.;.;.;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.41

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.84

T;T;.;T;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.093

T;T;T;T;T

MetaSVM

Uncertain

0.20

MutationAssessor

Benign

-0.67

N;.;.;.;N

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.36

N;N;N;.;.

REVEL

Uncertain

0.43

Sift

Benign

1.0

T;T;T;.;.

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0040

B;.;.;.;.

Vest4

0.11

MutPred

0.55

Loss of helix (P = 0.2271);.;.;.;Loss of helix (P = 0.2271);

MVP

0.61

MPC

0.91

ClinPred

0.091

GERP RS

5.0

Varity_R

0.044

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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