rs1553463602
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_001040142.2(SCN2A):c.5318C>A(p.Ala1773Glu) 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. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1773T) has been classified 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: 7.80
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 13 ACMG points.
PM1
In a repeat IV (size 298) in uniprot entity SCN2A_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) 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 chr2-165389123-G-A is described in Lovd as [Pathogenic].
PP2
Missense variant in the SCN2A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 362 curated pathogenic missense variants (we use a threshold of 10). The gene has 36 curated benign missense variants. Trascript score misZ: 8.7114 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.99
PP5
Variant 2-165389124-C-A is Pathogenic according to our data. Variant chr2-165389124-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 984900.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SCN2A | ENST00000375437.7 | c.5318C>A | p.Ala1773Glu | missense_variant | Exon 27 of 27 | 5 | NM_001040142.2 | ENSP00000364586.2 | ||
| SCN2A | ENST00000631182.3 | c.5318C>A | p.Ala1773Glu | missense_variant | Exon 27 of 27 | 5 | NM_001371246.1 | ENSP00000486885.1 | ||
| SCN2A | ENST00000283256.10 | c.5318C>A | p.Ala1773Glu | missense_variant | Exon 27 of 27 | 1 | ENSP00000283256.6 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 11 Pathogenic:1
Feb 27, 2024
Service de Génétique Médicale, Centre Hospitalier Universitaire de Nice-Université Côte d'Azur
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Complex neurodevelopmental disorder Pathogenic:1
Nov 10, 2017
GenomeConnect - Simons Searchlight
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: provider interpretation
Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2017-11-10 and interpreted as Pathogenic. Variant was initially reported on 2017-04-02 by GTR ID of laboratory name Medical University of Warsaw Department of Medical Genetics Laboratory . The reporting laboratory might also submit to ClinVar. -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
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
H;H;.;H;H;H;H
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 helix (P = 0.132);Gain of helix (P = 0.132);.;Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
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