rs147891446

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001040142.2(SCN2A):c.2034A>G(p.Thr678Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00746 in 1,613,978 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0077 ( 80 hom. )

Consequence

SCN2A
NM_001040142.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.0120

Publications

4 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 2-165326869-A-G is Benign according to our data. Variant chr2-165326869-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.012 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00523 (796/152336) while in subpopulation SAS AF = 0.0166 (80/4830). AF 95% confidence interval is 0.0136. There are 4 homozygotes in GnomAd4. There are 369 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 796 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2 link	c.2034A>G	p.Thr678Thr	synonymous_variant	Exon 13 of 27	ENST00000375437.7	NP_001035232.1	Q99250-1
SCN2A	NM_001371246.1 link	c.2034A>G	p.Thr678Thr	synonymous_variant	Exon 13 of 27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN2A	ENST00000375437.7 link	c.2034A>G	p.Thr678Thr	synonymous_variant	Exon 13 of 27	5	NM_001040142.2	ENSP00000364586.2	Q99250-1
SCN2A	ENST00000631182.3 link	c.2034A>G	p.Thr678Thr	synonymous_variant	Exon 13 of 27	5	NM_001371246.1	ENSP00000486885.1	Q99250-2
SCN2A	ENST00000283256.10 link	c.2034A>G	p.Thr678Thr	synonymous_variant	Exon 13 of 27	1		ENSP00000283256.6	Q99250-1

Frequencies

GnomAD3 genomes

AF:

0.00523

AC:

796

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.0362

Gnomad AMR

AF:

0.00445

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0165

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00729

Gnomad OTH

AF:

0.00527

GnomAD2 exomes

AF:

0.00655

AC:

1647

AN:

251352

AF XY:

0.00735

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00240

Gnomad ASJ exome

AF:

0.00387

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00296

Gnomad NFE exome

AF:

0.00739

Gnomad OTH exome

AF:

0.00490

GnomAD4 exome

AF:

0.00769

AC:

11237

AN:

1461642

Hom.:

Cov.:

AF XY:

0.00807

AC XY:

5865

AN XY:

727108

show subpopulations

African (AFR)

AF:

0.00114

AC:

AN:

33468

American (AMR)

AF:

0.00228

AC:

102

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00421

AC:

110

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39664

South Asian (SAS)

AF:

0.0185

AC:

1598

AN:

86252

European-Finnish (FIN)

AF:

0.00367

AC:

196

AN:

53402

Middle Eastern (MID)

AF:

0.0128

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00786

AC:

8741

AN:

1111856

Other (OTH)

AF:

0.00624

AC:

377

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

593

1187

1780

2374

2967

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

328

656

984

1312

1640

<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:

0.00523

AC:

796

AN:

152336

Hom.:

Cov.:

AF XY:

0.00495

AC XY:

369

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

41578

American (AMR)

AF:

0.00444

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.0166

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00226

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00729

AC:

496

AN:

68030

Other (OTH)

AF:

0.00522

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

116

155

194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00620

Hom.:

Bravo

AF:

0.00484

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:4

Nov 14, 2012

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 30, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 25, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 17, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 07, 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

Jan 30, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

7.8

(source)

DANN

Benign

0.81

PhyloP100

-0.012

Mutation Taster

=69/31

polymorphism

(source)

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

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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