rs751979396

Positions:

• chr12-51794533-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS2 BS1

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 NM_014191.4 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:2
• Conservation: PhyloP100: 1.89

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.4687A>G	p.Ile1563Val	missense_variant	26/27	ENST00000627620.5
SCN8A	NM_014191.4	c.4687A>G	p.Ile1563Val	missense_variant	26/27	ENST00000354534.11
SCN8A	NM_001177984.3	c.4564A>G	p.Ile1522Val	missense_variant	25/26
SCN8A	NM_001369788.1	c.4564A>G	p.Ile1522Val	missense_variant	25/26

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152224 Hom.: 1 Cov.: 31

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: 2 AN: 249196 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135198

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: 12 AN: 1461710 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727138

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: 2 AN: 152224 Hom.: 1 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74364

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.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:1

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

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Benign	0.25
DEOGEN2	Uncertain	0.57	D;.;.;.;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.84	T;T;.;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.093	T;T;T;T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	-0.67	N;.;.;.;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
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	T
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

Other links and lift over

dbSNP: rs751979396; hg19: chr12-52188317;