12-51765746-G-T

Variant names:

• chr12-51765746-G-T
• rs1057524820
• NM_001330260.2:c.2620G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_001330260.2(SCN8A):​c.2620G>T​(p.Ala874Ser) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN8A NM_001330260.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U: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.

• 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, 0.806
• PP5: Variant 12-51765746-G-T is Pathogenic according to our data. Variant chr12-51765746-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 393169.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.2620G>T	p.Ala874Ser	missense_variant	Exon 16 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.2620G>T	p.Ala874Ser	missense_variant	Exon 16 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.2620G>T	p.Ala874Ser	missense_variant	Exon 16 of 26		NP_001171455.1
SCN8A	NM_001369788.1	c.2620G>T	p.Ala874Ser	missense_variant	Exon 16 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.2620G>T	p.Ala874Ser	missense_variant	Exon 16 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.2620G>T	p.Ala874Ser	missense_variant	Exon 16 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.2653G>T	p.Ala885Ser	missense_variant	Exon 15 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.2620G>T	p.Ala874Ser	missense_variant	Exon 15 of 25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Jan 24, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The A874S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A874S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). It has been identified as a confirmed de novo variant at GeneDx. The A874S variant is a non-conservative amino acid substitution that alters a conserved position predicted to be within the intracellular loop between the S4 and S5 transmembrane segments of the second homologous domain. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic. -

Developmental and epileptic encephalopathy, 13 Pathogenic:1

May 10, 2017

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Apr 01, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces alanine with serine at codon 874 of the SCN8A protein (p.Ala874Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SCN8A-related conditions. ClinVar contains an entry for this variant (Variation ID: 393169). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;.;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.3	L;L;L;.;L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.9	D;D;D;.;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;D;D;.;.
Sift4G	Uncertain	0.059	T;T;T;T;T
Polyphen		1.0	D;.;.;.;.
Vest4		0.62
MutPred		0.63		Gain of glycosylation at A874 (P = 0.231);Gain of glycosylation at A874 (P = 0.231);Gain of glycosylation at A874 (P = 0.231);.;Gain of glycosylation at A874 (P = 0.231);
MVP		0.97
MPC		3.0
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.74
gMVP		0.95

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: rs1057524820; hg19: chr12-52159530;