12-51699663-T-C

Variant names:

• chr12-51699663-T-C
• rs878853250
• NM_001330260.2:c.800T>C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001330260.2(SCN8A):​c.800T>C​(p.Leu267Ser) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN8A NM_001330260.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.02
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 13

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• cognitive impairment with or without cerebellar ataxia

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• seizures, benign familial infantile, 5

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile convulsions and choreoathetosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myoclonus, familial, 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain 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, developmental and epileptic encephalopathy, 13, undetermined early-onset epileptic encephalopathy, benign familial infantile epilepsy, complex neurodevelopmental disorder, seizures, benign familial infantile, 5, cognitive impairment with or without cerebellar ataxia, infantile convulsions and choreoathetosis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• PP5: Variant 12-51699663-T-C is Pathogenic according to our data. Variant chr12-51699663-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 236207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.800T>C	p.Leu267Ser	missense_variant	Exon 7 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.800T>C	p.Leu267Ser	missense_variant	Exon 7 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.800T>C	p.Leu267Ser	missense_variant	Exon 7 of 26		NP_001171455.1
SCN8A	NM_001369788.1	c.800T>C	p.Leu267Ser	missense_variant	Exon 7 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.800T>C	p.Leu267Ser	missense_variant	Exon 7 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.800T>C	p.Leu267Ser	missense_variant	Exon 7 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.800T>C	p.Leu267Ser	missense_variant	Exon 6 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.800T>C	p.Leu267Ser	missense_variant	Exon 6 of 25	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, severe;C0543888:Epileptic encephalopathy;C0557874:Global developmental delay;C1836508:Generalized tonic seizure;C1836829:Developmental stagnation at onset of seizures;C1836830:Developmental regression Pathogenic:1

-

Lyon Laboratory, Cold Spring Harbor Laboratory

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy Pathogenic:1

Oct 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine with serine at codon 267 of the SCN8A protein (p.Leu267Ser). The leucine residue is highly conserved and there is a large physicochemical difference between leucine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (PMID: 27900360, 30109124). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 236207). 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"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1

Jan 16, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This substitution is predicted to be within the transmembrane segment S5 of the first homologous domain; This variant is associated with the following publications: (PMID: 30109124, 32090326, 31887642, 27900360) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;D;.;.;.;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;.;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	.;H;H;H;H;H;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.9	.;D;D;D;.;.;N
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;D;D;D;.;.;T
Sift4G	Pathogenic	0.0	.;D;D;D;D;D;D
Polyphen		0.98, 1.0	.;D;.;.;D;.;.
Vest4		0.92, 0.95, 0.95, 0.95, 0.94
MutPred		0.67		Loss of stability (P = 0.014);Loss of stability (P = 0.014);Loss of stability (P = 0.014);Loss of stability (P = 0.014);Loss of stability (P = 0.014);Loss of stability (P = 0.014);.;
MVP		0.99
MPC		2.4
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.94
gMVP		0.98
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs878853250; hg19: chr12-52093447;