NM_001330260.2:c.1228G>A

Variant names:

• chr12-51705510-G-A
• NM_001330260.2:c.1228G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001330260.2(SCN8A):​c.1228G>A​(p.Val410Met) 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: 32)
• Consequence: SCN8A NM_001330260.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P: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 Likely_pathogenic. Variant got 7 ACMG points.

• 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, 0.918
• PP5: Variant 12-51705510-G-A is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.1228G>A	p.Val410Met	missense_variant	Exon 10 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.1228G>A	p.Val410Met	missense_variant	Exon 10 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.1228G>A	p.Val410Met	missense_variant	Exon 10 of 26		NP_001171455.1
SCN8A	NM_001369788.1	c.1228G>A	p.Val410Met	missense_variant	Exon 10 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.1228G>A	p.Val410Met	missense_variant	Exon 10 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.1228G>A	p.Val410Met	missense_variant	Exon 10 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.1228G>A	p.Val410Met	missense_variant	Exon 9 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.1228G>A	p.Val410Met	missense_variant	Exon 9 of 25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Sep 27, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1228G>A (p.V410M) alteration is located in exon 10 (coding exon 9) of the SCN8A gene. This alteration results from a G to A substitution at nucleotide position 1228, causing the valine (V) at amino acid position 410 to be replaced by a methionine (M). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant occurred de novo in two individuals with epilepsy (Peng, 2019; Ambry internal data). An alteration affecting the same amino acid, p.V410L, was reported de novo in an individual with epileptic encephalopathy (Larsen, 2015). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;D;.;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D;.;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	.;M;M;M;M;M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.0	.;D;D;D;.;.;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;D;D;D;.;.;.
Sift4G	Pathogenic	0.0	.;D;D;D;D;D;D
Polyphen		0.99, 1.0	.;D;.;.;D;.;.
Vest4		0.81, 0.83, 0.83, 0.83, 0.83
MutPred		0.64		Gain of disorder (P = 0.1175);Gain of disorder (P = 0.1175);Gain of disorder (P = 0.1175);Gain of disorder (P = 0.1175);Gain of disorder (P = 0.1175);Gain of disorder (P = 0.1175);.;
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.78
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-52099294;