2-165386976-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_001040142.2(SCN2A):c.4782G>C(p.Trp1594Cys) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W1594R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 10.0

Genes affected

SCN2A (HGNC:10588): (sodium voltage-gated channel alpha subunit 2) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with four repeat domains, each of which is composed of six membrane-spanning segments, and one or more regulatory beta subunits. Voltage-gated sodium channels function in the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. Allelic variants of this gene are associated with seizure disorders and autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001040142.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-165386974-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, SCN2A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 2-165386976-G-C is Pathogenic according to our data. Variant chr2-165386976-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 383825.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2A	NM_001040142.2	c.4782G>C	p.Trp1594Cys	missense_variant	26/27	ENST00000375437.7
SCN2A	NM_001371246.1	c.4782G>C	p.Trp1594Cys	missense_variant	26/27	ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7	c.4782G>C	p.Trp1594Cys	missense_variant	26/27	5	NM_001040142.2	P1
SCN2A	ENST00000631182.3	c.4782G>C	p.Trp1594Cys	missense_variant	26/27	5	NM_001371246.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 17, 2017

A W1594C variant that is likely pathogenic has been identified in the SCN2A gene. A different nucleotide substitution (c.4782 G>T) resulting in the same amino acid change, W1594C, has been reported previously as a de novo variant in an individual with neonatal seizures, intellectual disability, and polymicrogyria; this individual also had a de novo variant in the RAI1 gene (Poirier et al., 2013). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W1594C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a conserved position predicted to be within transmembrane segment S3 in the fourth homologous domain of the SCN2A protein, and missense variants in nearby residues (G1593R, D1598G) have been reported in the Human Gene Mutation Database in association with SCN2A-related disorders (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2016

The p.W1594C variant (also known as c.4782G>C), located in coding exon 25 of the SCN2A gene, results from a G to C substitution at nucleotide position 4782. The tryptophan at codon 1594 is replaced by cysteine, an amino acid with highly dissimilar properties. In one study which performed exome sequencing on individuals with cortical malformations, this alteration was detected as a de novo occurrence in an individual with neonatal seizures and perisylvian polymicrogyria who also carried the de novo RAI1 p.L855P alteration. It is unclear whether this individual's epilepsy phenotype is due to their genotype or their cortical malformation (Poirier K et al. Nat. Genet., 2013 Jun;45:639-47).This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	30
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;.;D;.;D;D;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D;.;.;.;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	5.1	H;H;.;H;H;H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-11	D;.;.;.;.;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.;.;.;.;D;D
Sift4G	Pathogenic	0.0	D;.;.;D;.;D;D
Polyphen		1.0	D;D;.;D;D;D;D
Vest4		0.97
MutPred		0.86		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.97
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.94
gMVP		1.0

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: rs1057521747; hg19: chr2-166243486;