rs587780448

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5

The NM_001040142.2(SCN2A):​c.1280C>A​(p.Ala427Asp) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A427V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

SCN2A
NM_001040142.2 missense

Scores

17
1
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1O:1

Conservation

PhyloP100: 7.91
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 Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a hotspot region, there are 10 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 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, 0.866
PP5
Variant 2-165314005-C-A is Pathogenic according to our data. Variant chr2-165314005-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130212.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN2ANM_001040142.2 linkc.1280C>A p.Ala427Asp missense_variant Exon 10 of 27 ENST00000375437.7 NP_001035232.1 Q99250-1
SCN2ANM_001371246.1 linkc.1280C>A p.Ala427Asp missense_variant Exon 10 of 27 ENST00000631182.3 NP_001358175.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN2AENST00000375437.7 linkc.1280C>A p.Ala427Asp missense_variant Exon 10 of 27 5 NM_001040142.2 ENSP00000364586.2 Q99250-1
SCN2AENST00000631182.3 linkc.1280C>A p.Ala427Asp missense_variant Exon 10 of 27 5 NM_001371246.1 ENSP00000486885.1 Q99250-2
SCN2AENST00000283256.10 linkc.1280C>A p.Ala427Asp missense_variant Exon 10 of 27 1 ENSP00000283256.6 Q99250-1
SCN2AENST00000424833.5 linkc.1280C>A p.Ala427Asp missense_variant Exon 10 of 11 1 ENSP00000406454.2 F6U291

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:1
Sep 27, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be in the cytoplasmic loop between the first and second homologous domains; This variant is associated with the following publications: (PMID: 37578743, O'Connor2023[Case report]) -

Jul 23, 2013
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Complex neurodevelopmental disorder Other:1
-
Channelopathy-Associated Epilepsy Research Center
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.52
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.97
.;D;.;T;.;D;D;.
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;.;D;.;.;.;D
M_CAP
Pathogenic
0.69
D
MetaRNN
Pathogenic
0.87
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.2
.;M;M;.;M;M;M;M
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-5.6
D;D;.;.;.;.;D;D
REVEL
Pathogenic
0.81
Sift
Pathogenic
0.0
D;D;.;.;.;.;D;D
Sift4G
Pathogenic
0.0
D;D;.;.;D;.;D;D
Polyphen
1.0
.;D;D;.;D;D;D;D
Vest4
0.88, 0.87, 0.87
MutPred
0.44
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);Gain of relative solvent accessibility (P = 0.1259);
MVP
0.99
ClinPred
1.0
D
GERP RS
5.8
Varity_R
0.97
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

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

Other links and lift over

dbSNP: rs587780448; hg19: chr2-166170515; API