rs121917750

Positions:

• chr2-165386881-C-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001040142.2(SCN2A):​c.4687C>G​(p.Leu1563Val) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 1.18

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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a repeat IV (size 298) in uniprot entity SCN2A_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 2-165386881-C-G is Pathogenic according to our data. Variant chr2-165386881-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 12877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.4687C>G	p.Leu1563Val	missense_variant	26/27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.4687C>G	p.Leu1563Val	missense_variant	26/27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.4687C>G	p.Leu1563Val	missense_variant	26/27	5	NM_001040142.2	ENSP00000364586	P1
SCN2A	ENST00000631182.3	c.4687C>G	p.Leu1563Val	missense_variant	26/27	5	NM_001371246.1	ENSP00000486885

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 13, 2022

This missense change has been observed in individual(s) with benign familial neonatal-infantile seizures (PMID: 12243921). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1563 of the SCN2A protein (p.Leu1563Val). ClinVar contains an entry for this variant (Variation ID: 12877). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects SCN2A function (PMID: 17021166, 17467289, 18479388). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 12, 2024

Published functional studies demonstrate that L1563V causes a gain of channel function and increases neuronal excitability in neonatal sodium channels (PMID: 18479388, 17467289); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This substitution is predicted to be within the transmembrane segment S2 of the fourth homologous domain; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15301839, 18537643, 22029951, 3508699, 17467289, 17021166, 28256214, 28717674, 32090326, 32291436, 34425903, 29691040, 35637276, 32845893, 31904120, 33769100, 29844171, 31995133, 30813884, 12243921, 18479388) -

Seizures, benign familial infantile, 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 14, 2002

- -

Complex neurodevelopmental disorder Other:1

not provided, no classification provided

literature only

Channelopathy-Associated Epilepsy Research Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;T;.;D;D;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D;.;D;.;.;.;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;H;.;H;H;H;H
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.7	D;.;.;.;.;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;.;.;.;.;D;D
Sift4G	Uncertain	0.014	D;.;.;D;.;D;D
Polyphen		1.0	D;P;.;P;D;D;P
Vest4		0.78
MutPred		0.79		Loss of stability (P = 0.126);Loss of stability (P = 0.126);.;Loss of stability (P = 0.126);Loss of stability (P = 0.126);Loss of stability (P = 0.126);Loss of stability (P = 0.126);
MVP		0.99
ClinPred		1.0	D
GERP RS		-0.82
Varity_R		0.83
gMVP		0.99

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: rs121917750; hg19: chr2-166243391;