2-165389123-G-A

Position:

• chr2-165389123-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2_Supporting PS3 PS4 PS2_Moderate PM1_Strong

This summary comes from the ClinGen Evidence Repository: The c.5317G>A (NM_001040142.2) variant in SCN2A is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 1773 (p.Ala1773Thr). This variant has been reported in 9 probands with complex neurodevelopmental disorder (PMIDs: 34758253, 33000761, 28947817, 29655203, 31440721, 31785789, 34469436, 32400968, 35431799), including as a de novo occurrence with confirmed parental relationships in 2 individual(s) (PMIDs: 31785789, 32400968) and as a de novo occurrence with assumed parental relationships in 2 individuals PMID:33000761, 35431799). This variant is absent from gnomAD v2.1.1. Whole-cell patch-clamp recordings of voltage-gated Na+ currents in HEK293T cell in showed a significant hyperpolarizing shift in the voltage dependence of the activation curve and a depolarizing shift of steady-state fast inactivation accompanied by decreased current density indicating that this variant impacts protein function (PMIDs: 32400968, 32400968). This variant resides within a region of SCN2A that is defined as a mutational hotspot and/or critical functional domain by the ClinGen Epilepsy Sodium Channel VCEP (PM1). In summary, this variant meets the criteria to be classified as pathogenic for complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS3, PS4, PS2, PM1, PM2_Supporting. (Epilepsy Sodium Channel VCEP specifications v1.0; approved 5/9/23). LINK:https://erepo.genome.network/evrepo/ui/classification/CA318033/MONDO:0100038/068

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:10 O:1
• Conservation: PhyloP100: 9.86

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 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.
• PS4: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.5317G>A	p.Ala1773Thr	missense_variant	27/27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.5317G>A	p.Ala1773Thr	missense_variant	27/27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.5317G>A	p.Ala1773Thr	missense_variant	27/27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.5317G>A	p.Ala1773Thr	missense_variant	27/27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.5317G>A	p.Ala1773Thr	missense_variant	27/27	1		ENSP00000283256.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Developmental and epileptic encephalopathy, 11 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	May 14, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 34469436, 28947817, PS1). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Ala1773Val) has been reported as pathogenic (PMID:28379373, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94, 3Cnet: 0.996, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2023	Published functional studies demonstrate that the variant results in a loss of function effect on the protein (Miao et al., 2020); This substitution is predicted to be within the transmembrane segment S6 of the fourth homologous domain; Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28256214, 34469436, 34758253, 29655203, 24267886, 20196795, 23849776, 32400968, 33000761, 31785789, 31440721, 35431799, 27824329, 28379373, 24077912) -

Complex neurodevelopmental disorder Pathogenic:1 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.5317G>A (NM_001040142.2) variant in SCN2A is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 1773 (p.Ala1773Thr). This variant has been reported in 9 probands with complex neurodevelopmental disorder (PMIDs: 34758253, 33000761, 28947817, 29655203, 31440721, 31785789, 34469436, 32400968, 35431799), including as a de novo occurrence with confirmed parental relationships in 2 individual(s) (PMIDs: 31785789, 32400968) and as a de novo occurrence with assumed parental relationships in 2 individuals PMID: 33000761, 35431799). This variant is absent from gnomAD v2.1.1. Whole-cell patch-clamp recordings of voltage-gated Na+ currents in HEK293T cell in showed a significant hyperpolarizing shift in the voltage dependence of the activation curve and a depolarizing shift of steady-state fast inactivation accompanied by decreased current density indicating that this variant impacts protein function (PMIDs: 32400968, 32400968). This variant resides within a region of SCN2A that is defined as a mutational hotspot and/or critical functional domain by the ClinGen Epilepsy Sodium Channel VCEP (PM1). In summary, this variant meets the criteria to be classified as pathogenic for complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS3, PS4, PS2, PM1, PM2_Supporting. (Epilepsy Sodium Channel VCEP specifications v1.0; approved 5/9/23). -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2015

- -

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

Nov 26, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN2A function (PMID: 32400968). 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: 207024). This missense change has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (PMID: 32400968; Invitae). 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 alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1773 of the SCN2A protein (p.Ala1773Thr). -

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	0.91
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;T;.;D;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;.;D;.;.;.;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;H;.;H;H;H;H
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.7	D;.;.;.;.;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;.;.;.;D;D
Sift4G	Pathogenic	0.0010	D;.;.;D;.;D;D
Polyphen		1.0	D;D;.;D;D;D;D
Vest4		0.93
MutPred		0.77		Gain of glycosylation at A1773 (P = 0.0607);Gain of glycosylation at A1773 (P = 0.0607);.;Gain of glycosylation at A1773 (P = 0.0607);Gain of glycosylation at A1773 (P = 0.0607);Gain of glycosylation at A1773 (P = 0.0607);Gain of glycosylation at A1773 (P = 0.0607);
MVP		0.99
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.82
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: rs796053162; hg19: chr2-166245633;