rs794727152

Positions:

• chr2-165342465-G-A
• chr2-165342465-G-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2_Supporting PS2 PS3 PP3_Moderate PM1

This summary comes from the ClinGen Evidence Repository: The c.2558G>A variant in SCN2A is a missense variant predicted to cause subsitution of arginine by glutamine at amino acid 853 (p.Arg853Gln). This variant has been identified as a de novo occurrence with confirmed parental relationships in at least 4 individual(s) identified in the published literature (PMIDs: 23935176 , 23934111, 31139143, 28708303], with additional evidence published reports available (PS2). It is absent from gnomAD v2.1.1 (PM2_Supporting). Heterologous expression assay with voltage clamping showed a decrease in peak current of 51%, which is below the threshold of 72.1%, evidence that correlates with PS3. It is a missense variant that resides within a pathogenic enriched region that is defined as a mutational hotspot (PM1). The computational predictor REVEL gives a score of 0.95, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. In summary, this variant meets the criteria to be classified as PATHOGENIC for AUTOSOMAL DOMINANT COMPLEX NEURODEVELOPMENTAL DISORDER based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS2, PS3, PP3_Moderate, PM2_Supporting. (Epilepsy Sodium Channel VCEP specifications version 1.0) LINK:https://erepo.genome.network/evrepo/ui/classification/CA210022/MONDO:0100038/068

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12 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 13 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.2558G>A	p.Arg853Gln	missense_variant	15/27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.2558G>A	p.Arg853Gln	missense_variant	15/27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.2558G>A	p.Arg853Gln	missense_variant	15/27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.2558G>A	p.Arg853Gln	missense_variant	15/27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.2558G>A	p.Arg853Gln	missense_variant	15/27	1		ENSP00000283256.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Developmental and epileptic encephalopathy, 11 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris	Jan 06, 2017	Intellectual disability.severe; epilepsy (spasms); dysmorphism -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 19, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Jun 18, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 31, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2021	Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26482601, 32090326, 24866042, 25772804, 23935176, 25459969, 23934111, 29056246, 28708303, 28628100, 28379373, 29186148, 30174244, 29844171, 30619928, 29655203, 31139143, 31558572, 32860008, 32005694, 33278787, 31031587, 31175295, 33731876, 34093402, 34287911) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 18, 2015	- -

Complex neurodevelopmental disorder Pathogenic:2 Other:1

not provided, no classification provided	literature only	Channelopathy-Associated Epilepsy Research Center	-	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel, Clingen	May 09, 2023	The c.2558G>A variant in SCN2A is a missense variant predicted to cause subsitution of arginine by glutamine at amino acid 853 (p.Arg853Gln). This variant has been identified as a de novo occurrence with confirmed parental relationships in at least 4 individual(s) identified in the published literature (PMIDs: 23935176 , 23934111, 31139143, 28708303], with additional evidence published reports available (PS2). It is absent from gnomAD v2.1.1 (PM2_Supporting). Heterologous expression assay with voltage clamping showed a decrease in peak current of 51%, which is below the threshold of 72.1%, evidence that correlates with PS3. It is a missense variant that resides within a pathogenic enriched region that is defined as a mutational hotspot (PM1). The computational predictor REVEL gives a score of 0.95, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. In summary, this variant meets the criteria to be classified as PATHOGENIC for AUTOSOMAL DOMINANT COMPLEX NEURODEVELOPMENTAL DISORDER based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS2, PS3, PP3_Moderate, PM2_Supporting. (Epilepsy Sodium Channel VCEP specifications version 1.0) -
Pathogenic, no assertion criteria provided	provider interpretation	GenomeConnect - Simons Searchlight	Jan 16, 2019	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2019-01-16 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. -

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 07, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 853 of the SCN2A protein (p.Arg853Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with West syndrome (PMID: 23935176, 25772804, 28379373, 29186148). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 194555). 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. For these reasons, this variant has been classified as Pathogenic. -

West syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Neurology Department, Shenzhen Children's Hospital

Feb 16, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;.;T;.;D;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;.;D;.;.;.;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;H;.;H;H;H;H
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.6	D;.;.;.;.;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;.;.;.;.;D;D
Sift4G	Uncertain	0.0020	D;.;.;D;.;D;D
Polyphen		1.0	D;D;.;D;D;D;D
Vest4		0.94
MutPred		0.89		Loss of MoRF binding (P = 0.0329);Loss of MoRF binding (P = 0.0329);.;Loss of MoRF binding (P = 0.0329);Loss of MoRF binding (P = 0.0329);Loss of MoRF binding (P = 0.0329);Loss of MoRF binding (P = 0.0329);
MVP		1.0
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.91
gMVP		1.0

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: rs794727152; hg19: chr2-166198975;