chr12-51769308-C-T

Position:

chr12-51769308-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001330260.2(SCN8A):c.3345C>T(p.Ser1115Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,596,552 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 (★★).

Frequency

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

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SCN8A
NM_001330260.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0240

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:

SCN8A (HGNC:):

SCN8A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2 linkuse as main transcript	c.3345C>T	p.Ser1115Ser	synonymous_variant	17/27	ENST00000627620.5	NP_001317189.1	Q9UQD0-2Q6B4S4
SCN8A	NM_014191.4 linkuse as main transcript	c.3345C>T	p.Ser1115Ser	synonymous_variant	17/27	ENST00000354534.11	NP_055006.1	Q9UQD0-1
SCN8A	NM_001177984.3 linkuse as main transcript	c.3345C>T	p.Ser1115Ser	synonymous_variant	17/26		NP_001171455.1	Q9UQD0-5
SCN8A	NM_001369788.1 linkuse as main transcript	c.3345C>T	p.Ser1115Ser	synonymous_variant	17/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN8A	ENST00000354534.11 linkuse as main transcript	c.3345C>T	p.Ser1115Ser	synonymous_variant	17/27	1	NM_014191.4	ENSP00000346534.4	Q9UQD0-1
SCN8A	ENST00000627620.5 linkuse as main transcript	c.3345C>T	p.Ser1115Ser	synonymous_variant	17/27	5	NM_001330260.2	ENSP00000487583.2	Q9UQD0-2
SCN8A	ENST00000599343.5 linkuse as main transcript	c.3378C>T	p.Ser1126Ser	synonymous_variant	16/26	5		ENSP00000476447.3	Q9UQD0-3
SCN8A	ENST00000355133.7 linkuse as main transcript	c.3345C>T	p.Ser1115Ser	synonymous_variant	16/25	1		ENSP00000347255.4	Q9UQD0-5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000124

AC:

AN:

241600

Hom.:

AF XY:

0.0000153

AC XY:

AN XY:

130298

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:

0.0000355

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000912

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.0000118

AC:

AN:

1444438

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

715272

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000109

Gnomad4 OTH exome

AF:

0.0000504

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 29, 2022

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 586525). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. This variant is present in population databases (rs745966369, gnomAD 0.006%). This sequence change affects codon 1115 of the SCN8A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SCN8A protein. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.72

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.72

Position offset: -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