rs1553579305
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_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
NM_001040142.2 missense
Scores
16
2
1
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM1
?
In a hotspot region, there are 9 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;
PP2
?
Missense variant where missense usually causes diseases, SCN2A
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 | UniProt |
---|---|---|---|---|---|---|---|
SCN2A | NM_001040142.2 | c.2645G>A | p.Gly882Glu | missense_variant | 16/27 | ENST00000375437.7 | |
SCN2A | NM_001371246.1 | c.2645G>A | p.Gly882Glu | missense_variant | 16/27 | ENST00000631182.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN2A | ENST00000375437.7 | c.2645G>A | p.Gly882Glu | missense_variant | 16/27 | 5 | NM_001040142.2 | P1 | |
SCN2A | ENST00000631182.3 | c.2645G>A | p.Gly882Glu | missense_variant | 16/27 | 5 | NM_001371246.1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Complex neurodevelopmental disorder Pathogenic:1Other:1
not provided, no classification provided | literature only | Channelopathy-Associated Epilepsy Research Center | - | - - |
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. - |
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;T;.;D;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;.;.;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;.;M;M;M;M
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;.;.;.;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;.;.;.;.;D;D
Sift4G
Pathogenic
D;.;.;D;.;D;D
Polyphen
D;D;.;D;D;D;D
Vest4
MutPred
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
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at