rs1057518487

Variant names:

• chr12-51688775-T-C
• rs1057518487
• NM_014191.4:c.632T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_014191.4(SCN8A):​c.632T>C​(p.Val211Ala) 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: 32)
• Consequence: SCN8A NM_014191.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 8.02
• Publications: 3 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_014191.4
• 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: 10.278 (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, 0.772
• PP5: Variant 12-51688775-T-C is Pathogenic according to our data. Variant chr12-51688775-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 373565.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_014191.4	c.632T>C	p.Val211Ala	missense_variant	Exon 6 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001330260.2	c.615-230T>C		intron_variant	Intron 5 of 26	ENST00000627620.5	NP_001317189.1
SCN8A	NM_001177984.3	c.632T>C	p.Val211Ala	missense_variant	Exon 6 of 26		NP_001171455.1
SCN8A	NM_001369788.1	c.615-230T>C		intron_variant	Intron 5 of 25		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.632T>C	p.Val211Ala	missense_variant	Exon 6 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000599343.5	c.632T>C	p.Val211Ala	missense_variant	Exon 5 of 26	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.632T>C	p.Val211Ala	missense_variant	Exon 5 of 25	1		ENSP00000347255.4
SCN8A	ENST00000627620.5	c.615-230T>C		intron_variant	Intron 5 of 26	5	NM_001330260.2	ENSP00000487583.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Jun 13, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A novel V211A variant that is likely pathogenic has been identified in the SCN8A gene. The V211A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V211A variant is a conservative amino acid substitution that occurs at a conserved position predicted to alter a residue within the S3 of the helical transmembrane region of repeat I, and in silico analysis predicts this variant is probably damaging to the protein structure/function. It has been identified as a confirmed de novo variant in a patient referred for testing at GeneDx. Therefore, we interpret V211A as a likely pathogenic variant. -

Developmental and epileptic encephalopathy Pathogenic:1

Jun 19, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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"). This variant has been observed to be de novo in an individual affected with early infantile epileptic encephalopathy (PMID: 29121005). ClinVar contains an entry for this variant (Variation ID: 373565). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with alanine at codon 211 of the SCN8A protein (p.Val211Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	T;T;.;T
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;M;M;M
PhyloP100		8.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.9	D;D;D;.
REVEL	Pathogenic	0.85
Sift	Benign	0.040	D;D;D;.
Sift4G	Uncertain	0.019	D;D;D;D
Polyphen		0.91	P;.;.;.
Vest4		0.64
MutPred		0.73		Loss of stability (P = 0.0673);Loss of stability (P = 0.0673);Loss of stability (P = 0.0673);Loss of stability (P = 0.0673);
MVP		0.85
MPC		2.3
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.51
gMVP		0.95
Mutation Taster		=14/86	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: rs1057518487; hg19: chr12-52082559;