rs17183814

Positions:

chr2-165295879-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.56G>A variant in SCN2A is a missense variant predicted to cause substitution of arginine by lysine at amino acid 19 (p.Arg19Lys). This variant is present at an allele frequency of 8% of the total population in gnomAD (v2.1.1), with the highest sub-population allele frequency in the East Asian population with an AF of 15%, which exceeds the threshold of 0.01% to meet the stand-alone criterion for Benign (BA1). This variant has not been reported in the literature to date in an individual with a complex neurodevelopmental disorder (PS2_not met, PM6_not met, PS4_not met). The variant has not been functionally characterized, and is not located in a pathogenic enriched region defined as a mutational hotspot (PM1_not met). 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 (Epilepsy Sodium Channel VCEP specifications, version 1.0; approved 6/13/23). LINK:https://erepo.genome.network/evrepo/ui/classification/CA155062/MONDO:0100038/068

Frequency

Genomes: 𝑓 0.064 ( 359 hom., cov: 32)

Exomes 𝑓: 0.076 ( 4634 hom. )

Consequence

SCN2A
NM_001040142.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:8

Conservation

PhyloP100: 2.48

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 -8 ACMG points.

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.56G>A	p.Arg19Lys	missense_variant	2/27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1 linkuse as main transcript	c.56G>A	p.Arg19Lys	missense_variant	2/27	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.56G>A	p.Arg19Lys	missense_variant	2/27	5	NM_001040142.2	ENSP00000364586	P1	Q99250-1
SCN2A	ENST00000631182.3 linkuse as main transcript	c.56G>A	p.Arg19Lys	missense_variant	2/27	5	NM_001371246.1	ENSP00000486885		Q99250-2

Frequencies

GnomAD3 genomes

AF:

0.0638

AC:

9706

AN:

152150

Hom.:

358

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0296

Gnomad AMI

AF:

0.132

Gnomad AMR

AF:

0.0962

Gnomad ASJ

AF:

0.0652

Gnomad EAS

AF:

0.138

Gnomad SAS

AF:

0.126

Gnomad FIN

AF:

0.0381

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0704

Gnomad OTH

AF:

0.0641

GnomAD3 exomes

AF:

0.0843

AC:

21148

AN:

250808

Hom.:

1097

AF XY:

0.0845

AC XY:

11453

AN XY:

135540

show subpopulations

Gnomad AFR exome

AF:

0.0297

Gnomad AMR exome

AF:

0.127

Gnomad ASJ exome

AF:

0.0620

Gnomad EAS exome

AF:

0.151

Gnomad SAS exome

AF:

0.121

Gnomad FIN exome

AF:

0.0424

Gnomad NFE exome

AF:

0.0694

Gnomad OTH exome

AF:

0.0700

GnomAD4 exome

AF:

0.0764

AC:

111622

AN:

1461794

Hom.:

4634

Cov.:

AF XY:

0.0776

AC XY:

56442

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.0273

Gnomad4 AMR exome

AF:

0.120

Gnomad4 ASJ exome

AF:

0.0644

Gnomad4 EAS exome

AF:

0.0987

Gnomad4 SAS exome

AF:

0.116

Gnomad4 FIN exome

AF:

0.0452

Gnomad4 NFE exome

AF:

0.0741

Gnomad4 OTH exome

AF:

0.0743

GnomAD4 genome

AF:

0.0637

AC:

9706

AN:

152268

Hom.:

359

Cov.:

AF XY:

0.0645

AC XY:

4800

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0295

Gnomad4 AMR

AF:

0.0963

Gnomad4 ASJ

AF:

0.0652

Gnomad4 EAS

AF:

0.138

Gnomad4 SAS

AF:

0.126

Gnomad4 FIN

AF:

0.0381

Gnomad4 NFE

AF:

0.0704

Gnomad4 OTH

AF:

0.0639

Alfa

AF:

0.0697

Hom.:

770

Bravo

AF:

0.0666

TwinsUK

AF:

0.0698

AC:

259

ALSPAC

AF:

0.0820

AC:

316

ESP6500AA

AF:

0.0336

AC:

148

ESP6500EA

AF:

0.0716

AC:

616

ExAC

AF:

0.0818

AC:

9935

Asia WGS

AF:

0.114

AC:

397

AN:

3478

EpiCase

AF:

0.0700

EpiControl

AF:

0.0670

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2016

This alteration is classified as 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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Seizures, benign familial infantile, 3

Benign:1

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. -

Complex neurodevelopmental disorder

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel, Clingen

Jun 13, 2023

The c.56G>A variant in SCN2A is a missense variant predicted to cause substitution of arginine by lysine at amino acid 19 (p.Arg19Lys). This variant is present at an allele frequency of 8% of the total population in gnomAD (v2.1.1), with the highest sub-population allele frequency in the East Asian population with an AF of 15%, which exceeds the threshold of 0.01% to meet the stand-alone criterion for Benign (BA1). This variant has not been reported in the literature to date in an individual with a complex neurodevelopmental disorder (PS2_not met, PM6_not met, PS4_not met). The variant has not been functionally characterized, and is not located in a pathogenic enriched region defined as a mutational hotspot (PM1_not met). 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 (Epilepsy Sodium Channel VCEP specifications, version 1.0; approved 6/13/23). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Benign

0.96

DEOGEN2

Uncertain

0.50

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

Eigen

Benign

0.082

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.74

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

MetaRNN

Benign

0.0015

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

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.8

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

MutationTaster

Benign

0.85

P;P;P;P

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.3

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

REVEL

Uncertain

0.33

Sift

Benign

0.21

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

Sift4G

Benign

0.48

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

Polyphen

0.0010, 0.0020

.;B;B;B;B;B;B

Vest4

0.090, 0.062, 0.072, 0.088

ClinPred

0.011

GERP RS

5.5

Varity_R

0.38

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.20

Position offset: 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