rs746163041

Positions:

• chr2-165344869-C-A
• chr2-165344869-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001040142.2(SCN2A):​c.2877C>A​(p.Cys959*) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2A NM_001040142.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.67

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-165344869-C-A is Pathogenic according to our data. Variant chr2-165344869-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 410979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.2877C>A	p.Cys959*	stop_gained	16/27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.2877C>A	p.Cys959*	stop_gained	16/27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.2877C>A	p.Cys959*	stop_gained	16/27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.2877C>A	p.Cys959*	stop_gained	16/27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.2877C>A	p.Cys959*	stop_gained	16/27	1		ENSP00000283256.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 11 Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Aug 25, 2022

The heterozygous p.Cys959Ter variant in SCN2A was identified in 1 individual with a neurodevelopmental disorder including autism, global developmental delay, absent speech, and stereotypy via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Neurodev Study (https://www.neurodevproject.org/). Trio exome analysis showed this variant to be de novo. The p.Cys959Ter variant in SCN2A was found to be de novo in 2 individuals with neurodevelopmental disorders (PMID: 22495306, 24859339), and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID#: 410979) and has been interpreted as pathogenic by Invitae and GenomeConnect - Simons Searchlight. In vitro functional studies provide some evidence that the p.Cys959Ter variant may impact protein function (PMID: 28256214). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 959, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the SCN2A gene is an established disease mechanism in neurodevelopmental disorders. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant complex neurodevelopmental disorder. ACMG/AMP Criteria applied: PVS1, PS2_moderate, PM2_supporting, PS3_supporting, PS4_supporting (Richards 2015). -

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2016

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SCN2A are known to be pathogenic. This particular variant has been reported in the literature (PMID: 22495306, 24859339). This sequence change creates a premature translational stop signal at codon 959 (p.Cys959*) of the SCN2A gene. It is expected to result in an absent or disrupted protein product. -

Complex neurodevelopmental disorder Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

GenomeConnect - Simons Searchlight

Jun 10, 2016

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-06-10 and interpreted as Pathogenic. Variant was initially reported by the University of Washington TIGER study and was later confirmed by GeneDx. The reporting laboratory might also submit to ClinVar. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.92	D
Vest4		0.96
GERP RS		4.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs746163041; hg19: chr2-166201379;