rs879255699

chr12-51705510-G-Cchr12-51705510-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Moderate

The NM_014191.4(SCN8A):c.1228G>C(p.Val410Leu) 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 not provided (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V410A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN8A NM_014191.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 10.0

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 13 ACMG points.

• PS1: Transcript NM_014191.4 (SCN8A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 802857
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 chr12-51705510-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2231762.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, SCN8A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.1228G>C	p.Val410Leu	missense_variant	10/27	ENST00000627620.5
SCN8A	NM_014191.4	c.1228G>C	p.Val410Leu	missense_variant	10/27	ENST00000354534.11
SCN8A	NM_001177984.3	c.1228G>C	p.Val410Leu	missense_variant	10/26
SCN8A	NM_001369788.1	c.1228G>C	p.Val410Leu	missense_variant	10/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.1228G>C	p.Val410Leu	missense_variant	10/27	1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.1228G>C	p.Val410Leu	missense_variant	10/27	5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Developmental and epileptic encephalopathy, 13 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;T;T;.;T;D;T
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
Polyphen		0.031, 1.0	.;B;.;.;D;.;.
Vest4		0.85, 0.90, 0.90, 0.90, 0.89
MutPred		0.58		Loss of catalytic residue at V410 (P = 0.0326);Loss of catalytic residue at V410 (P = 0.0326);Loss of catalytic residue at V410 (P = 0.0326);Loss of catalytic residue at V410 (P = 0.0326);Loss of catalytic residue at V410 (P = 0.0326);Loss of catalytic residue at V410 (P = 0.0326);.;
MVP		0.95
MPC		2.1
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.66
gMVP		0.98

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

Other links and lift over

dbSNP: rs879255699; hg19: chr12-52099294;