rs1553579305

Positions:

• chr2-165344637-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_001040142.2(SCN2A):​c.2645G>A​(p.Gly882Glu) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 8.01

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 11 ACMG points.

• PM1: In a transmembrane_region Helical; Name=S5 of repeat II (size 18) in uniprot entity SCN2A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001040142.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN2A. . Trascript score misZ 8.7114 (greater than threshold 3.09). GenCC has associacion of gene with seizures, benign familial infantile, 3, Dravet syndrome, benign familial neonatal-infantile seizures, malignant migrating partial seizures of infancy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 11, developmental and epileptic encephalopathy, West syndrome, benign familial infantile epilepsy, episodic ataxia, type 9.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 2-165344637-G-A is Pathogenic according to our data. Variant chr2-165344637-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 520571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-165344637-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.2645G>A	p.Gly882Glu	missense_variant	16/27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.2645G>A	p.Gly882Glu	missense_variant	16/27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.2645G>A	p.Gly882Glu	missense_variant	16/27	5	NM_001040142.2	ENSP00000364586	P1
SCN2A	ENST00000631182.3	c.2645G>A	p.Gly882Glu	missense_variant	16/27	5	NM_001371246.1	ENSP00000486885

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Complex neurodevelopmental disorder Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	provider interpretation	GenomeConnect - Simons Searchlight	Feb 16, 2016	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-02-16 and interpreted as Pathogenic. Variant was initially reported on 2014-09-25 by GTR ID of laboratory name 61756. The reporting laboratory might also submit to ClinVar. -
not provided, no classification provided	literature only	Channelopathy-Associated Epilepsy Research Center	-	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 2014

The c.2645G>A (p.G882E) alteration is located in exon 16 (coding exon 15) of the SCN2A gene. This alteration results from a G to A substitution at nucleotide position 2645, causing the glycine (G) at amino acid position 882 to be replaced by a glutamic acid (E). The alteration is not observed in healthy cohorts:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the SCN2A c.2645G>A alteration was not observed among 6,502 individuals tested. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). The altered nucleotide is conserved throughout evolution:_x000D_ The c.2645G nucleotide is conserved throughout available vertebrate species except the lamprey, which has the nucleotide C at this position._x000D_ The altered amino acid is conserved throughout evolution:_x000D_ The p.G882 amino acid is conserved throughout available vertebrate species, except the opossum and the lamprey. The alteration is predicted deleterious by in silico models:_x000D_ The p.G882E alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses._x000D_ The alteration is predicted not to affect splicing by in silico models:_x000D_ Based on BDGP and ESEfinder splice site in silico tools, this alteration does not have any significant effect on the native acceptor/donor splice site; however, direct evidence is unavailable. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;T;.;D;D;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;.;D;.;.;.;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M;M;.;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-7.6	D;.;.;.;.;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.;.;.;.;D;D
Sift4G	Pathogenic	0.0010	D;.;.;D;.;D;D
Polyphen		0.99	D;D;.;D;D;D;D
Vest4		0.73
MutPred		0.77		Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);.;Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);
MVP		1.0
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.99
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: rs1553579305; hg19: chr2-166201147; COSMIC: COSV51850507;