rs1135401806

chr12-51789393-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_014191.4(SCN8A):c.4394A>T(p.Asp1465Val) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1465N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN8A NM_014191.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.32

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_014191.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-51789392-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 934328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, SCN8A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928
• PP5: Variant 12-51789393-A-T is Pathogenic according to our data. Variant chr12-51789393-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 431135.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.4394A>T	p.Asp1465Val	missense_variant	24/27	ENST00000627620.5
SCN8A	NM_014191.4	c.4394A>T	p.Asp1465Val	missense_variant	24/27	ENST00000354534.11
SCN8A	NM_001177984.3	c.4271A>T	p.Asp1424Val	missense_variant	23/26
SCN8A	NM_001369788.1	c.4271A>T	p.Asp1424Val	missense_variant	23/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.4394A>T	p.Asp1465Val	missense_variant	24/27	1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.4394A>T	p.Asp1465Val	missense_variant	24/27	5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 13 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris

Jan 06, 2017

Intellectual disability, moderate; epilepsy with early onset < 2 years; microcephaly -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;.;.;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;.;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;.;.;.;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.8	D;D;D;.;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;.;.
Sift4G	Uncertain	0.015	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.89
MutPred		0.56		Loss of disorder (P = 0.0629);.;.;.;Loss of disorder (P = 0.0629);
MVP		0.99
MPC		2.4
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.92
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1135401806; hg19: chr12-52183177;