rs2228980

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BS2BA1

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

Publications

13 publications found

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 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

SCN2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2 link	c.2723A>G	p.Lys908Arg	missense_variant	Exon 16 of 27	ENST00000375437.7	NP_001035232.1	Q99250-1
SCN2A	NM_001371246.1 link	c.2723A>G	p.Lys908Arg	missense_variant	Exon 16 of 27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN2A	ENST00000375437.7 link	c.2723A>G	p.Lys908Arg	missense_variant	Exon 16 of 27	5	NM_001040142.2	ENSP00000364586.2	Q99250-1
SCN2A	ENST00000631182.3 link	c.2723A>G	p.Lys908Arg	missense_variant	Exon 16 of 27	5	NM_001371246.1	ENSP00000486885.1	Q99250-2
SCN2A	ENST00000283256.10 link	c.2723A>G	p.Lys908Arg	missense_variant	Exon 16 of 27	1		ENSP00000283256.6	Q99250-1

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

GnomAD2 exomes

AF:

0.00437

AC:

1098

AN:

251494

AF XY:

0.00470

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 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

African (AFR)

AF:

0.000836

AC:

AN:

33480

American (AMR)

AF:

0.00326

AC:

146

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00161

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.00472

AC:

407

AN:

86258

European-Finnish (FIN)

AF:

0.00107

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00312

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00643

AC:

7147

AN:

1112008

Other (OTH)

AF:

0.00510

AC:

308

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

492

984

1477

1969

2461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

268

536

804

1072

1340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00368

AC:

561

AN:

152248

Hom.:

Cov.:

AF XY:

0.00334

AC XY:

249

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00130

AC:

AN:

41556

American (AMR)

AF:

0.00432

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00373

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000848

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00578

AC:

393

AN:

68004

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

116

145

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00517

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

Jun 20, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 27, 2014

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 16, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 15, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SCN2A: PM5, PP2, BS2 -

Seizures, benign familial infantile, 3

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jun 12, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Dec 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Complex neurodevelopmental disorder

Benign:1

May 09, 2024

ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel, Clingen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

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

(source)

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

PhyloP100

4.1

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

Mutation Taster

=98/2

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over