rs17183814

Variant names:

• chr2-165295879-G-A
• rs17183814
• NM_001040142.2:c.56G>A

Variant summary

Our verdict is Benign. The variant received -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
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: 2.48
• Publications: 75 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: Benign. The variant received -8 ACMG points.

• 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	c.56G>A	p.Arg19Lys	missense_variant	Exon 2 of 27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.56G>A	p.Arg19Lys	missense_variant	Exon 2 of 27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.56G>A	p.Arg19Lys	missense_variant	Exon 2 of 27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.56G>A	p.Arg19Lys	missense_variant	Exon 2 of 27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.56G>A	p.Arg19Lys	missense_variant	Exon 2 of 27	1		ENSP00000283256.6
SCN2A	ENST00000424833.5	c.56G>A	p.Arg19Lys	missense_variant	Exon 2 of 11	1		ENSP00000406454.2

Frequencies

GnomAD3 genomes AF: 0.0638 AC: 9706 AN: 152150 Hom.: 358 Cov.: 32

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

GnomAD2 exomes AF: 0.0843 AC: 21148 AN: 250808 AF XY: 0.0845

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 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.: 32 AF XY: 0.0776 AC XY: 56442 AN XY: 727194

African (AFR) AF: 0.0273 AC: 914 AN: 33480

American (AMR) AF: 0.120 AC: 5348 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0644 AC: 1684 AN: 26134

East Asian (EAS) AF: 0.0987 AC: 3919 AN: 39692

South Asian (SAS) AF: 0.116 AC: 10045 AN: 86254

European-Finnish (FIN) AF: 0.0452 AC: 2416 AN: 53412

Middle Eastern (MID) AF: 0.0692 AC: 399 AN: 5768

European-Non Finnish (NFE) AF: 0.0741 AC: 82409 AN: 1111972

Other (OTH) AF: 0.0743 AC: 4488 AN: 60388

GnomAD4 genome AF: 0.0637 AC: 9706 AN: 152268 Hom.: 359 Cov.: 32 AF XY: 0.0645 AC XY: 4800 AN XY: 74456

African (AFR) AF: 0.0295 AC: 1226 AN: 41562

American (AMR) AF: 0.0963 AC: 1472 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0652 AC: 226 AN: 3468

East Asian (EAS) AF: 0.138 AC: 714 AN: 5184

South Asian (SAS) AF: 0.126 AC: 607 AN: 4828

European-Finnish (FIN) AF: 0.0381 AC: 404 AN: 10608

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0704 AC: 4786 AN: 68012

Other (OTH) AF: 0.0639 AC: 135 AN: 2114

Alfa AF: 0.0693 Hom.: 1609

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

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Inborn genetic diseases Benign:1

Jan 08, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Seizures, benign familial infantile, 3 Benign:1

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. -

Complex neurodevelopmental disorder Benign:1

May 07, 2024

ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel, Clingen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	33
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	D
LIST_S2	Benign	0.74	T;T;.;.;.;.;T
MetaRNN	Benign	0.0015	T;T;T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.8	.;L;L;L;L;L;L
PhyloP100		2.5
PrimateAI	Uncertain	0.67	T
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	T
GERP RS		5.5
Varity_R		0.38
gMVP		0.70
Mutation Taster		=84/16	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17183814; hg19: chr2-166152389; COSMIC: COSV51834563;