rs794727152

Variant names:

• chr2-165342465-G-A
• rs794727152
• NM_001040142.2:c.2558G>A

Your query was ambiguous. Multiple possible variants found:

• 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 PM1 PP3_Moderate

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:13 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 rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.2558G>A	p.Arg853Gln	missense_variant	Exon 15 of 27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.2558G>A	p.Arg853Gln	missense_variant	Exon 15 of 27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.2558G>A	p.Arg853Gln	missense_variant	Exon 15 of 27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.2558G>A	p.Arg853Gln	missense_variant	Exon 15 of 27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.2558G>A	p.Arg853Gln	missense_variant	Exon 15 of 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:13 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Developmental and epileptic encephalopathy, 11 Pathogenic:5

Jun 18, 2013

UCLA Clinical Genomics Center, UCLA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 26, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.95 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 1.00 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000194555 /PMID: 23935176). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 28379373). A different missense change at the same codon (p.Arg853Pro) has been reported to be associated with SCN2A related disorder (ClinVar ID: VCV001451854). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 06, 2017

Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intellectual disability.severe; epilepsy (spasms); dysmorphism -

Oct 19, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:3

Oct 31, 2017

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Complex neurodevelopmental disorder Pathogenic:2 Other:1

May 09, 2023

ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel, Clingen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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) -

Jan 16, 2019

GenomeConnect - Simons Searchlight

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

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. -

-

Channelopathy-Associated Epilepsy Research Center

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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

May 18, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 194555). 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. This variant is not present in population databases (gnomAD no frequency). 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). -

West syndrome Pathogenic:1

Feb 16, 2022

Neurology Department, Shenzhen Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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;