2-165386976-G-C

Variant names:

• chr2-165386976-G-C
• rs1057521747
• NM_001040142.2:c.4782G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 10 ACMG points: 10P and 0B. PM5_Supporting PS1_Moderate PM6 PM2_Supporting PS4_Moderate PP3_Moderate

This summary comes from the ClinGen Evidence Repository: The c.4782G>C variant in SCN2A is a missense variant predicted to cause substitution of tryptophan by cysteine at amino acid 1594 (p.Trp1594Cys). The variant has been identified in multiple individuals meeting criteria for complex neurodevelopmental disorder (PS4, PM6)(PMID:34004075, internal lab contributors). It is absent from the population database gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.924, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. The same amino acid change (p.Trp1594Cys), resulting from a different nucleotide change[c.4782G>T](PMID:35365919, PMID:23603762) is classified as likely pathogenic for complex neurodevelopmental disorder by the ClinGen Epilepsy Sodium Channel VCEP(PS1_Moderate). Additionally, another missense variant in the same codon c.4780T>A, p.Trp1594Arg reaches likely pathogenic based on current criteria (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS4_Moderate, PM6, PS1_Moderate, PM2_Supporting, PP3_Moderate, PM5_Supporting. (version 1.0; November 26, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16603919/MONDO:0100038/068

• 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 Likely_pathogenic. Variant got 10 ACMG points.

• PS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.4782G>C	p.Trp1594Cys	missense_variant	Exon 26 of 27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.4782G>C	p.Trp1594Cys	missense_variant	Exon 26 of 27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.4782G>C	p.Trp1594Cys	missense_variant	Exon 26 of 27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.4782G>C	p.Trp1594Cys	missense_variant	Exon 26 of 27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.4782G>C	p.Trp1594Cys	missense_variant	Exon 26 of 27	1		ENSP00000283256.6

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

Jul 17, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 01, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
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;