Variant chr12-51790479-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3PP5_Moderate

The NM_014191.4(SCN8A):c.4501C>A(p.Gln1501Lys) 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 Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Consequence

SCN8A
NM_014191.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.91

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 8 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_014191.4

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.772

PP5

Variant 12-51790479-C-A is Pathogenic according to our data. Variant chr12-51790479-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 377169.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SCN8A	NM_001330260.2 linkuse as main transcript	c.4501C>A	p.Gln1501Lys	missense_variant	25/27	ENST00000627620.5
SCN8A	NM_014191.4 linkuse as main transcript	c.4501C>A	p.Gln1501Lys	missense_variant	25/27	ENST00000354534.11
SCN8A	NM_001177984.3 linkuse as main transcript	c.4378C>A	p.Gln1460Lys	missense_variant	24/26
SCN8A	NM_001369788.1 linkuse as main transcript	c.4378C>A	p.Gln1460Lys	missense_variant	24/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11 linkuse as main transcript	c.4501C>A	p.Gln1501Lys	missense_variant	25/27	1	NM_014191.4	P4	Q9UQD0-1
SCN8A	ENST00000627620.5 linkuse as main transcript	c.4501C>A	p.Gln1501Lys	missense_variant	25/27	5	NM_001330260.2	A1	Q9UQD0-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jan 05, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;.;.;.;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;.;D;D

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.77

D;D;D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Uncertain

2.5

M;.;.;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.7

D;D;D;.;.

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

D;D;D;.;.

Sift4G

Benign

0.16

T;T;T;T;T

Polyphen

0.96

D;.;.;.;.

Vest4

0.61

MutPred

0.40

Gain of methylation at Q1501 (P = 0.0037);.;.;.;Gain of methylation at Q1501 (P = 0.0037);

MVP

0.96

MPC

1.9

ClinPred

1.0

GERP RS

4.6

Varity_R

0.89

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