2-165389558-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP2BP4

The NM_001040142.2(SCN2A):​c.5752C>G​(p.Arg1918Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

SCN2A
NM_001040142.2 missense

Scores

1
8
10

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.04
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 Uncertain_significance. Variant got 4 ACMG points.

PM1
In a topological_domain Cytoplasmic (size 229) in uniprot entity SCN2A_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) 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.
BP4
Computational evidence support a benign effect (MetaRNN=0.41390577).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SCN2ANM_001040142.2 linkuse as main transcriptc.5752C>G p.Arg1918Gly missense_variant 27/27 ENST00000375437.7 NP_001035232.1
SCN2ANM_001371246.1 linkuse as main transcriptc.5752C>G p.Arg1918Gly missense_variant 27/27 ENST00000631182.3 NP_001358175.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCN2AENST00000375437.7 linkuse as main transcriptc.5752C>G p.Arg1918Gly missense_variant 27/275 NM_001040142.2 ENSP00000364586 P1Q99250-1
SCN2AENST00000631182.3 linkuse as main transcriptc.5752C>G p.Arg1918Gly missense_variant 27/275 NM_001371246.1 ENSP00000486885 Q99250-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.10
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.70
D;.;T;.;D;D;.
Eigen
Benign
-0.062
Eigen_PC
Benign
0.094
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.86
D;.;D;.;.;.;D
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.41
T;T;T;T;T;T;T
MetaSVM
Uncertain
0.40
D
MutationAssessor
Benign
1.7
L;L;.;L;L;L;L
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-2.1
N;.;.;.;.;N;N
REVEL
Uncertain
0.60
Sift
Benign
0.30
T;.;.;.;.;T;T
Sift4G
Benign
0.14
T;.;.;T;.;T;T
Polyphen
0.038
B;B;.;B;B;B;B
Vest4
0.31
MutPred
0.44
Loss of stability (P = 0.0074);Loss of stability (P = 0.0074);.;Loss of stability (P = 0.0074);Loss of stability (P = 0.0074);Loss of stability (P = 0.0074);Loss of stability (P = 0.0074);
MVP
0.91
ClinPred
0.61
D
GERP RS
5.0
Varity_R
0.39
gMVP
0.91

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: rs139899756; hg19: chr2-166246068; API