rs796053126

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_001040142.2(SCN2A):​c.2995G>A​(p.Glu999Lys) 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. E999V) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)
Failed GnomAD Quality Control

Consequence

SCN2A
NM_001040142.2 missense

Scores

14
3
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 10.0
Variant links:
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 17 ACMG points.

PM1
In a topological_domain Cytoplasmic (size 226) in uniprot entity SCN2A_HUMAN there are 5 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 chrnull-null-null-null is described in UniProt as null.
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, 0.878
PP5
Variant 2-165354267-G-A is Pathogenic according to our data. Variant chr2-165354267-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 206981.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
SCN2ANM_001040142.2 linkuse as main transcriptc.2995G>A p.Glu999Lys missense_variant 17/27 ENST00000375437.7 NP_001035232.1 Q99250-1
SCN2ANM_001371246.1 linkuse as main transcriptc.2995G>A p.Glu999Lys missense_variant 17/27 ENST00000631182.3 NP_001358175.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCN2AENST00000375437.7 linkuse as main transcriptc.2995G>A p.Glu999Lys missense_variant 17/275 NM_001040142.2 ENSP00000364586.2 Q99250-1
SCN2AENST00000631182.3 linkuse as main transcriptc.2995G>A p.Glu999Lys missense_variant 17/275 NM_001371246.1 ENSP00000486885.1 Q99250-2
SCN2AENST00000283256.10 linkuse as main transcriptc.2995G>A p.Glu999Lys missense_variant 17/271 ENSP00000283256.6 Q99250-1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
152102
Hom.:
0
Cov.:
32
FAILED QC
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
152218
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74424
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 11 Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingNeuroMeGen, Hospital Clinico Santiago de Compostela-- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 06, 2020This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Complex neurodevelopmental disorder Pathogenic:1Other:1
not provided, no classification providedliterature onlyChannelopathy-Associated Epilepsy Research Center-- -
Pathogenic, no assertion criteria providedprovider interpretationGenomeConnect - Simons SearchlightJul 14, 2016Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-07-14 and interpreted as Pathogenic. Variant was initially reported on 2015-07-31 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar. -
Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 27, 2023ClinVar contains an entry for this variant (Variation ID: 206981). This missense change has been observed in individual(s) with early onset epileptic encephalopathy (PMID: 23935176, 26648591, 26993267, 27867041, 28379373). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 999 of the SCN2A protein (p.Glu999Lys). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN2A protein function. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxJul 25, 2017The E999K variant has been reported previously as a de novo variant in multiple individuals with Ohtahara syndrome, early infantile epileptic encephaopathy, and severe intellectual disability (Nakamura et al., 2013, Allen et al., 2015, Trump et al., 2016). The E999K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E999K 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 alters a conserved position in the intracellular loop between the second and third transmembrane domains (Shi et al., 2012), and other missense variants have been reported in this region of the protein in association with epilepsy. A missense change at the same codon (E999V) has been reported in association with SCN2A-related disorder (Stenson et al., 2014, Trump et al., 2016). In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, E999K is considered a pathogenic variant. -
Epilepsy of infancy with migrating focal seizures Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingNeurology Department, Shenzhen Children's HospitalFeb 16, 2022- -
West syndrome Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingNeurology Department, Shenzhen Children's HospitalFeb 16, 2022- -
Developmental and epileptic encephalopathy, 30 Pathogenic:1
Pathogenic, no assertion criteria providedresearchDepartment of Neurology, Children’s Hospital of Chongqing Medical University-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.75
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.040
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.82
D;.;T;.;D;D;.
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.93
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;.;D;.;.;.;D
M_CAP
Pathogenic
0.69
D
MetaRNN
Pathogenic
0.88
D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.88
D
MutationAssessor
Pathogenic
3.9
H;H;.;H;H;H;H
PrimateAI
Pathogenic
0.86
D
PROVEAN
Uncertain
-3.7
D;.;.;.;.;D;D
REVEL
Pathogenic
0.70
Sift
Uncertain
0.0010
D;.;.;.;.;D;D
Sift4G
Benign
0.065
T;.;.;T;.;T;T
Polyphen
0.97
D;D;.;D;D;D;D
Vest4
0.57
MutPred
0.59
Gain of ubiquitination at E999 (P = 0.0082);Gain of ubiquitination at E999 (P = 0.0082);.;Gain of ubiquitination at E999 (P = 0.0082);Gain of ubiquitination at E999 (P = 0.0082);Gain of ubiquitination at E999 (P = 0.0082);Gain of ubiquitination at E999 (P = 0.0082);
MVP
0.94
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.88
gMVP
0.89

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs796053126; hg19: chr2-166210777; COSMIC: COSV51835030; API