rs1553568987

chr2-165314010-G-Achr2-165314010-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_001040142.2(SCN2A):c.1285G>A(p.Glu429Lys) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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 7 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001040142.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN2A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2A	NM_001040142.2	c.1285G>A	p.Glu429Lys	missense_variant	10/27	ENST00000375437.7
SCN2A	NM_001371246.1	c.1285G>A	p.Glu429Lys	missense_variant	10/27	ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7	c.1285G>A	p.Glu429Lys	missense_variant	10/27	5	NM_001040142.2	P1
SCN2A	ENST00000631182.3	c.1285G>A	p.Glu429Lys	missense_variant	10/27	5	NM_001371246.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 20, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SCN2A-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 429 of the SCN2A protein (p.Glu429Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;.;D;.;.;.;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.1	D;D;.;.;.;.;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0030	D;D;.;.;.;.;D;D
Sift4G	Uncertain	0.0060	D;D;.;.;D;.;D;D
Polyphen		1.0, 1.0	.;D;D;.;D;D;D;D
Vest4		0.69, 0.70, 0.70
MutPred		0.43		Gain of methylation at E429 (P = 0.0042);Gain of methylation at E429 (P = 0.0042);Gain of methylation at E429 (P = 0.0042);.;Gain of methylation at E429 (P = 0.0042);Gain of methylation at E429 (P = 0.0042);Gain of methylation at E429 (P = 0.0042);Gain of methylation at E429 (P = 0.0042);
MVP		0.98
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.89
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553568987; hg19: chr2-166170520;