2-165331362-T-C

Position:

• chr2-165331362-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_001040142.2(SCN2A):​c.2182T>C​(p.Cys728Arg) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02

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 Likely_pathogenic. Variant got 6 ACMG points.

• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888
• PP5: Variant 2-165331362-T-C is Pathogenic according to our data. Variant chr2-165331362-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 433097.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.2182T>C	p.Cys728Arg	missense_variant	14/27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.2182T>C	p.Cys728Arg	missense_variant	14/27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.2182T>C	p.Cys728Arg	missense_variant	14/27	5	NM_001040142.2	ENSP00000364586	P1
SCN2A	ENST00000631182.3	c.2182T>C	p.Cys728Arg	missense_variant	14/27	5	NM_001371246.1	ENSP00000486885

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Childhood epilepsy with centrotemporal spikes Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Jan 01, 2017

CAADphred>15 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.;T;.;D;D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	T;.;T;.;.;.;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M;.;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-11	D;.;.;.;.;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;.;.;.;.;D;D
Sift4G	Uncertain	0.037	D;.;.;D;.;D;D
Polyphen		1.0	D;P;.;P;D;D;P
Vest4		0.92
MutPred		0.39		Loss of catalytic residue at W729 (P = 7e-04);Loss of catalytic residue at W729 (P = 7e-04);.;Loss of catalytic residue at W729 (P = 7e-04);Loss of catalytic residue at W729 (P = 7e-04);Loss of catalytic residue at W729 (P = 7e-04);Loss of catalytic residue at W729 (P = 7e-04);
MVP		0.97
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.97

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: rs1553574522; hg19: chr2-166187872;