rs2228980

Positions:

chr2-165344715-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BA1BS2

This summary comes from the ClinGen Evidence Repository: The c.2723A>G variant in SCN2A is a missense variant predicted to cause substitution of lysine by arginine at amino acid 908 (p.Lys908Arg). This variant is present in gnomAD v2.1 at an allele frequency of 0.4% (1190/282874 alleles), with the highest sub-population minor allele frequency of 0.6% in the European (non-Finnish) population, which exceeds the ClinGen Epilepsy Sodium Channel threshold (0.01%) for BA1. Additionally, gnomAD v2.1.1 reports 7 individuals with this variant in a homozygous state (BS1). In summary, this variant meets the criteria to be classified as Benign for AUTOSOMAL DOMINANT COMPLEX NEURODEVELOPMENTAL DISORDER based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BA1, BS1 (VCEP specifications version 1.0; 6/13/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA155058/MONDO:0100038/068

Frequency

Genomes: 𝑓 0.0037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0056 ( 37 hom. )

Consequence

SCN2A
NM_001040142.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:15

Conservation

PhyloP100: 4.07

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

BA1

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 linkuse as main transcript	c.2723A>G	p.Lys908Arg	missense_variant	16/27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1 linkuse as main transcript	c.2723A>G	p.Lys908Arg	missense_variant	16/27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7 linkuse as main transcript	c.2723A>G	p.Lys908Arg	missense_variant	16/27	5	NM_001040142.2	ENSP00000364586	P1	Q99250-1
SCN2A	ENST00000631182.3 linkuse as main transcript	c.2723A>G	p.Lys908Arg	missense_variant	16/27	5	NM_001371246.1	ENSP00000486885		Q99250-2

Frequencies

GnomAD3 genomes

AF:

0.00368

AC:

560

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00578

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00437

AC:

1098

AN:

251494

Hom.:

AF XY:

0.00470

AC XY:

639

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.00306

Gnomad ASJ exome

AF:

0.00188

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00447

Gnomad FIN exome

AF:

0.000970

Gnomad NFE exome

AF:

0.00674

Gnomad OTH exome

AF:

0.00554

GnomAD4 exome

AF:

0.00558

AC:

8155

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00555

AC XY:

4039

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000836

Gnomad4 AMR exome

AF:

0.00326

Gnomad4 ASJ exome

AF:

0.00161

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00472

Gnomad4 FIN exome

AF:

0.00107

Gnomad4 NFE exome

AF:

0.00643

Gnomad4 OTH exome

AF:

0.00510

GnomAD4 genome

AF:

0.00368

AC:

561

AN:

152248

Hom.:

Cov.:

AF XY:

0.00334

AC XY:

249

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.00432

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.000848

Gnomad4 NFE

AF:

0.00578

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00525

Hom.:

Bravo

AF:

0.00432

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00640

AC:

ExAC

AF:

0.00491

AC:

596

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00523

EpiControl

AF:

0.00634

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 27, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 15, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SCN2A: PM5, PP2, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Seizures, benign familial infantile, 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11;C5394520:Episodic ataxia, type 9

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 02, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Complex neurodevelopmental disorder

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel, Clingen

May 09, 2024

The c.2723A>G variant in SCN2A is a missense variant predicted to cause substitution of lysine by arginine at amino acid 908 (p.Lys908Arg). This variant is present in gnomAD v2.1 at an allele frequency of 0.4% (1190/282874 alleles), with the highest sub-population minor allele frequency of 0.6% in the European (non-Finnish) population, which exceeds the ClinGen Epilepsy Sodium Channel threshold (0.01%) for BA1. Additionally, gnomAD v2.1.1 reports 7 individuals with this variant in a homozygous state (BS1). In summary, this variant meets the criteria to be classified as Benign for AUTOSOMAL DOMINANT COMPLEX NEURODEVELOPMENTAL DISORDER based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BA1, BS1 (VCEP specifications version 1.0; 6/13/2023) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;.;T;.;D;D;.

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.75

T;.;T;.;.;.;T

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.010

T;T;T;T;T;T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.3

L;L;.;L;L;L;L

MutationTaster

Benign

0.68

D;D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-2.2

N;.;.;.;.;N;N

REVEL

Uncertain

0.43

Sift

Uncertain

0.015

D;.;.;.;.;D;D

Sift4G

Benign

0.24

T;.;.;T;.;T;T

Polyphen

1.0

D;B;.;B;D;D;B

Vest4

0.24

MVP

0.97

ClinPred

0.024

GERP RS

5.7

Varity_R

0.63

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over