rs796053180

Positions:

• chr2-165313992-G-C
• chr2-165313992-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS1 PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001040142.2(SCN2A):​c.1267G>C​(p.Val423Leu) 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 Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Synonymous variant affecting the same amino acid position (i.e. V423V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O: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 Pathogenic. Variant got 19 ACMG points.

• PS1: Transcript NM_001040142.2 (SCN2A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 1072191
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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, 0.929
• PP5: Variant 2-165313992-G-C is Pathogenic according to our data. Variant chr2-165313992-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 207052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2A	NM_001040142.2	c.1267G>C	p.Val423Leu	missense_variant	10/27	ENST00000375437.7
SCN2A	NM_001371246.1	c.1267G>C	p.Val423Leu	missense_variant	10/27	ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7	c.1267G>C	p.Val423Leu	missense_variant	10/27	5	NM_001040142.2	P1
SCN2A	ENST00000631182.3	c.1267G>C	p.Val423Leu	missense_variant	10/27	5	NM_001371246.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 11 Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Mendelics	Apr 28, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 19, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 31, 2021	The SCN2A c.1267G>C variant is classified as PATHOGENIC (PS1, PS2, PS3, PS4-moderate, PM2) The SCN2A c.1267G>C variant is a single nucleotide change in exon 10/27 of the SCN2A gene, which is predicted to change the amino acid valine at position 423 in the protein to leucine. The same p.Val423Leu variant has been reported de novo in two unrelated patients with Ohtahara syndrome (PMID: 28379373). Patient 10 presented at day 1 with myoclonic and apnoeic seizures, while Patient 33 presented at day 6 with tonic clonic seizures. Both of these probands progressed to developing tonic and tonic-clonic seizures respectively, and EEGs showed a suppression burst pattern, and multifocal spikes. Both patients had a high pharmacoresistance including lack of response to treatment of one or more sodium channel blockers. The p.Val423Leu variant was assessed using whole cell patch-clamping in tsA201 kidney cells, which showed an increase in sodium channel activity with gain-of-function (PMID: 28379373) (PS3). This variant has been identified as de novo in this family with no family history of this condition (PS2). This variant results in the same amino acid change as another pathogenic variant, c.1267G>T, previously reported in ClinVar (Variation ID: 1072191) (PS1). This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs796053180). The variant has been reported as Likely Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 207052). This variant has not been reported in HGMD. Other Literature: PMID: 31924505. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 30, 2023

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN2A protein function. ClinVar contains an entry for this variant (Variation ID: 207052). This missense change has been observed in individual(s) with Ohtahara syndrome (PMID: 28379373). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 423 of the SCN2A protein (p.Val423Leu). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 27, 2014

p.Val423Leu (GTG>CTG): c.1267 G>C in exon 10 of the SCN2A gene (NM_021007.2). A V423L variant that is likely pathogenic has been identified in the SCN2A gene. The V423L variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V423Lvariant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution alters a highly conserved position in transmembrane segment S6 of the first homologous domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in INFANT-EPI panel(s). -

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	0.96
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;.;D;.;.;.;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.93	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	-2.8	D;D;.;.;.;.;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;.;.;.;.;D;D
Sift4G	Uncertain	0.0020	D;D;.;.;D;.;D;D
Polyphen		1.0	.;D;D;.;D;D;D;D
Vest4		0.88, 0.86, 0.87
MutPred		0.77		Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);.;Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);
MVP		1.0
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.86
gMVP		0.99

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: rs796053180; hg19: chr2-166170502;