chr2-165389558-C-G

Position:

• chr2-165389558-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.04

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]

ACMG classification

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
SCN2A	NM_001040142.2	c.5752C>G	p.Arg1918Gly	missense_variant	27/27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.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
SCN2A	ENST00000375437.7	c.5752C>G	p.Arg1918Gly	missense_variant	27/27	5	NM_001040142.2	ENSP00000364586	P1
SCN2A	ENST00000631182.3	c.5752C>G	p.Arg1918Gly	missense_variant	27/27	5	NM_001371246.1	ENSP00000486885

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

Other links and lift over

dbSNP: rs139899756; hg19: chr2-166246068;