2-165310413-C-T

Variant names:

• chr2-165310413-C-T
• rs387906686
• NM_001040142.2:c.788C>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001040142.2(SCN2A):​c.788C>T​(p.Ala263Val) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A263P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:21
• Conservation: PhyloP100: 7.91
• Publications: 43 publications found

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]

SCN2A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• developmental and epileptic encephalopathy, 11

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• episodic ataxia, type 9

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• seizures, benign familial infantile, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• benign familial neonatal-infantile seizures

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 7 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-165310413-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2939257.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the SCN2A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 362 curated pathogenic missense variants (we use a threshold of 10). The gene has 36 curated benign missense variants. Trascript score misZ: 8.7114 (above the threshold of 3.09). GenCC associations: The gene is linked to genetic developmental and epileptic encephalopathy, episodic ataxia, type 9, seizures, benign familial infantile, 3, complex neurodevelopmental disorder, benign familial neonatal-infantile seizures, Dravet syndrome, infantile spasms, developmental and epileptic encephalopathy, 11, intellectual disability, benign familial infantile epilepsy, malignant migrating partial seizures of infancy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 2-165310413-C-T is Pathogenic according to our data. Variant chr2-165310413-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 29888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.788C>T	p.Ala263Val	missense_variant	Exon 7 of 27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.788C>T	p.Ala263Val	missense_variant	Exon 7 of 27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.788C>T	p.Ala263Val	missense_variant	Exon 7 of 27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.788C>T	p.Ala263Val	missense_variant	Exon 7 of 27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.788C>T	p.Ala263Val	missense_variant	Exon 7 of 27	1		ENSP00000283256.6
SCN2A	ENST00000424833.5	c.788C>T	p.Ala263Val	missense_variant	Exon 7 of 11	1		ENSP00000406454.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000469 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 03, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional analysis indicates A263V is a gain-of-function variant leading to neuronal hyperexcitability (PMID: 20956790); Not observed at significant frequency in large population cohorts (gnomAD); This substitution is predicted to be within the transmembrane segment S5 of the first homologous domain; 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: 26283219, 26645390, 24579881, 22029951, 27334371, 28379373, 30361185, 33084218, 32860008, 30928199, 31054490, 32488064, 33000761, 35982159, 32090326, 31440721, 32651551, 31175295, 32139178, 33057194, 36007526, 37432431, 20956790, 23550958, 27159988, 28065826) -

Jan 19, 2022

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been confirmed to occur de novo in multiple individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. In vitro analyses indicate this variant alters sodium channel function (PMID: 20956790). -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 03, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 11 Pathogenic:3

May 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 30, 2023

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: 0.92 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.97 (>=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: VCV000029888 /PMID: 20956790). The variant has been previously reported as de novo in a similarly affected individual (PMID: 20956790). Different missense changes at the same codon (p.Ala263Glu, p.Ala263Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000520403, VCV001070304 /PMID: 23935176). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Seizures, benign familial infantile, 3 Pathogenic:3

Aug 06, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 24, 2023

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2022

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SCN2A-related disorder Pathogenic:2

Nov 12, 2017

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SCN2A c.788C>T variant is predicted to result in the amino acid substitution p.Ala263Val. This variant has been reported to be inherited and de novo in several individuals with neonatal epilepsy, late-onset ataxia, and/or myoclonus & pain (see for example the index case, Liao et al 2010. PubMed ID: 20956790; and literature reviewed in, Schwarz N et al 2019. PubMed ID: 30928199). These studies and others demonstrate that this variant causes a gain of channel function and occurs in a 'hot-spot' for pathogenic SCN2A variants. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. This variant is interpreted as pathogenic. -

Infantile spasms Pathogenic:1

-

Department of Neurology, Children’s Hospital of Chongqing Medical University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Inborn genetic diseases Pathogenic:1

Jul 11, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.788C>T (p.A263V) alteration is located in exon 7 (coding exon 6) of the SCN2A gene. This alteration results from a C to T substitution at nucleotide position 788, causing the alanine (A) at amino acid position 263 to be replaced by a valine (V). for SCN2A-related seizure disorder; however, its clinical significance for SCN2A-related neurodevelopmental disorder is uncertain This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a heterozygous or de novo mutation in multiple individuals with clinical features including neonatal onset seizures of varying types, developmental delay, hypotonia, poor feeding, spasticity, abnormal EEG, abnormal MRI findings, and severe encephalopathy; of note, many individuals eventually became seizure free (Liao, 2010; Touma, 2013; Schwarz, 2015; Gorman, 2017; Wolff, 2017; Flor-Hirsch, 2018; Nashabat, 2019; Kim, 2020). Additionally, this variant has been reported as inherited from an apparently unaffected father in two brothers with generalized tonic-clonic seizures onset at the tenth day of life and at two months and with global delay and muscular hypotonia (Schwarz, 2019). This amino acid position is highly conserved in available vertebrate species. In multiple assays testing SCN2A function, including a knock-in mouse model, this variant showed abnormal results through the mechanism of altered channel function (Liao, 2010; Schattling, 2016; Berecki, 2022). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

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

Sep 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 263 of the SCN2A protein (p.Ala263Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SCN2A-related conditions (PMID: 20956790, 26645390, 27159988, 28065826). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 29888). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN2A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN2A function (PMID: 20956790). For these reasons, this variant has been classified as Pathogenic. -

Epileptic encephalopathy Pathogenic:1

Nov 16, 2016

Neurogenetics Laboratory - MEYER, AOU Meyer

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Episodic ataxia, type 9 Pathogenic:1

May 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Complex neurodevelopmental disorder Pathogenic:1

Apr 25, 2016

GenomeConnect - Simons Searchlight

Significance: Likely 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 2016-04-25 and interpreted as Likely Pathogenic. Variant was initially reported on 2014-12-17 by GTR ID of laboratory name 283396. The reporting laboratory might also submit to ClinVar. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;D;.;T;.;D;D;.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;.;D;.;.;.;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.6	.;H;H;.;H;H;H;H;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-4.0	D;D;.;.;.;.;D;D;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;.;.;.;.;D;D;.
Sift4G	Pathogenic	0.0010	D;D;.;.;D;.;D;D;D
Polyphen		1.0	.;D;D;.;D;D;D;D;.
Vest4		0.97, 0.97
MutPred		0.60		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		5.3
Varity_R		0.98
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387906686; hg19: chr2-166166923; COSMIC: COSV51834971;