rs1198276041

Positions:

chr12-51721790-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP6

The ENST00000354534.11(SCN8A):c.1880C>T(p.Ser627Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,610,220 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S627S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SCN8A
ENST00000354534.11 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 5.50

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

BP6

Variant 12-51721790-C-T is Benign according to our data. Variant chr12-51721790-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436671.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SCN8A	NM_001330260.2 linkuse as main transcript	c.1880C>T	p.Ser627Leu	missense_variant	12/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4 linkuse as main transcript	c.1880C>T	p.Ser627Leu	missense_variant	12/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3 linkuse as main transcript	c.1880C>T	p.Ser627Leu	missense_variant	12/26		NP_001171455.1
SCN8A	NM_001369788.1 linkuse as main transcript	c.1880C>T	p.Ser627Leu	missense_variant	12/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11 linkuse as main transcript	c.1880C>T	p.Ser627Leu	missense_variant	12/27	1	NM_014191.4	ENSP00000346534	P4	Q9UQD0-1
SCN8A	ENST00000627620.5 linkuse as main transcript	c.1880C>T	p.Ser627Leu	missense_variant	12/27	5	NM_001330260.2	ENSP00000487583	A1	Q9UQD0-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152220

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:

0.00

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

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1458000

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725388

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

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

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

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 23, 2020

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 missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SCN8A-related conditions. ClinVar contains an entry for this variant (Variation ID: 436671). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with leucine at codon 627 of the SCN8A protein (p.Ser627Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 13, 2023

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This substitution is predicted to be within the cytoplasmic loop between the first and second homologous domains -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

.;D;.;.;.;.;.

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

D;D;D;.;D;D;D

M_CAP

Pathogenic

0.55

MetaRNN

Uncertain

0.61

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.91

MutationAssessor

Uncertain

2.7

.;M;M;M;M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.7

.;D;D;D;.;.;.

REVEL

Uncertain

0.64

Sift

Uncertain

0.011

.;D;D;D;.;.;.

Sift4G

Benign

0.061

.;T;T;T;T;T;D

Polyphen

0.39, 0.022

.;B;.;.;B;.;.

Vest4

0.75, 0.76, 0.78, 0.82, 0.80

MutPred

0.32

Loss of phosphorylation at S627 (P = 0.0026);Loss of phosphorylation at S627 (P = 0.0026);Loss of phosphorylation at S627 (P = 0.0026);Loss of phosphorylation at S627 (P = 0.0026);Loss of phosphorylation at S627 (P = 0.0026);Loss of phosphorylation at S627 (P = 0.0026);.;

MVP

0.92

MPC

2.0

ClinPred

0.96

GERP RS

3.9

Varity_R

0.23

gMVP

0.83

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