rs1555225784

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP3

The NM_001330260.2(SCN8A):c.2563G>A(p.Ala855Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SCN8A
NM_001330260.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 8.15

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a repeat II (size 272) in uniprot entity SCN8A_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001330260.2

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the SCN8A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 213 curated pathogenic missense variants (we use a threshold of 10). The gene has 45 curated benign missense variants. Gene score misZ: 0.78755 (below the threshold of 3.09). Trascript score misZ: 10.436 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.748

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2 link	c.2563G>A	p.Ala855Thr	missense_variant	Exon 16 of 27	ENST00000627620.5	NP_001317189.1	Q9UQD0-2Q6B4S4
SCN8A	NM_014191.4 link	c.2563G>A	p.Ala855Thr	missense_variant	Exon 16 of 27	ENST00000354534.11	NP_055006.1	Q9UQD0-1
SCN8A	NM_001177984.3 link	c.2563G>A	p.Ala855Thr	missense_variant	Exon 16 of 26		NP_001171455.1	Q9UQD0-5
SCN8A	NM_001369788.1 link	c.2563G>A	p.Ala855Thr	missense_variant	Exon 16 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN8A	ENST00000354534.11 link	c.2563G>A	p.Ala855Thr	missense_variant	Exon 16 of 27	1	NM_014191.4	ENSP00000346534.4	Q9UQD0-1
SCN8A	ENST00000627620.5 link	c.2563G>A	p.Ala855Thr	missense_variant	Exon 16 of 27	5	NM_001330260.2	ENSP00000487583.2	Q9UQD0-2
SCN8A	ENST00000599343.5 link	c.2596G>A	p.Ala866Thr	missense_variant	Exon 15 of 26	5		ENSP00000476447.3	Q9UQD0-3
SCN8A	ENST00000355133.7 link	c.2563G>A	p.Ala855Thr	missense_variant	Exon 15 of 25	1		ENSP00000347255.4	Q9UQD0-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1430056

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

707112

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 855 of the SCN8A protein (p.Ala855Thr). This variant is not present in population databases (gnomAD no frequency). 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: 523504). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN8A protein function with a positive 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. -

Intellectual disability, moderate

Uncertain:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;.;.;.;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;.;D;D

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.75

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.7

L;L;L;.;L

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-3.9

D;D;D;.;.

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;D;D;.;.

Sift4G

Uncertain

0.014

D;D;D;D;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.59

MutPred

0.64

Loss of ubiquitination at K853 (P = 0.0997);Loss of ubiquitination at K853 (P = 0.0997);Loss of ubiquitination at K853 (P = 0.0997);.;Loss of ubiquitination at K853 (P = 0.0997);

MVP

0.98

MPC

3.1

ClinPred

0.99

GERP RS

3.6

Varity_R

0.84

gMVP

0.97

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