2-165090746-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1BP4BA1

This summary comes from the ClinGen Evidence Repository: The c.5407G>A variant in SCN3A is a missense variant predicted to cause substitution of Aspartic acid by Asparagine at amino acid 1803 (p.Asp1803Asn). The highest population minor allele frequency in gnomAD v2.1.1 is 0.01653 (143/8652 alleles) in East Asian population, which is higher than the ClinGen Epilepsy Sodium Channel threshold (0.0001) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.114, which is below the threshold of 0.183, evidence that does not predict a damaging effect on SCN3A function (BP4_moderate). This variant resides within a region of SCN3A that is defined as a mutational hotspot by the ClinGen sodium channel VCEP (PM1). Although there are both pathogenic and benign types of evidence for this variant, the high frequency of this variant in gnomAD strongly supports a benign classification, and the only evidence in support of pathogenicity is based on a prediction that this variant may lie in a mutational hotspot. In summary, this variant meets the criteria to be classified as Benign for autosomal dominant developmental and epileptic encephalopathy based on ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BA1, BP4, and PM1. (VCEP specifications version 1; 6/27/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA1938411/MONDO:0100062/069

Frequency

Genomes: 𝑓 0.00061 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00054 ( 5 hom. )

Consequence

SCN3A
NM_006922.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:3

Conservation

PhyloP100: 2.73

Publications

14 publications found

Variant links:

Genes affected

SCN3A (HGNC:10590): (sodium voltage-gated channel alpha subunit 3) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family, and is found in a cluster of five alpha subunit genes on chromosome 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

SCN3A Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina, ClinGen
developmental and epileptic encephalopathy, 62
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
epilepsy, familial focal, with variable foci 4
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SCN3A links:

ENSG00000236283 (HGNC:):

ENSG00000236283 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM1

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

BP4

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
SCN3A	NM_006922.4 link	c.5407G>A	p.Asp1803Asn	missense_variant	Exon 28 of 28	ENST00000283254.12	NP_008853.3	Q9NY46-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN3A	ENST00000283254.12 link	c.5407G>A	p.Asp1803Asn	missense_variant	Exon 28 of 28	1	NM_006922.4	ENSP00000283254.7		Q9NY46-3

Frequencies

GnomAD3 genomes

AF:

0.000612

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0153

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00137

AC:

344

AN:

251408

AF XY:

0.00128

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0160

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000544

AC:

795

AN:

1461846

Hom.:

Cov.:

AF XY:

0.000547

AC XY:

398

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0168

AC:

665

AN:

39700

South Asian (SAS)

AF:

0.00103

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111988

Other (OTH)

AF:

0.000530

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

134

202

269

336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000611

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41534

American (AMR)

AF:

0.000131

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0153

AC:

AN:

5166

South Asian (SAS)

AF:

0.00229

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.0000446

Hom.:

Bravo

AF:

0.000812

ExAC

AF:

0.00140

AC:

170

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy

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.5407G>A variant in SCN3A is a missense variant predicted to cause substitution of Aspartic acid by Asparagine at amino acid 1803 (p.Asp1803Asn). The highest population minor allele frequency in gnomAD v2.1.1 is 0.01653 (143/8652 alleles) in East Asian population, which is higher than the ClinGen Epilepsy Sodium Channel threshold (0.0001) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.114, which is below the threshold of 0.183, evidence that does not predict a damaging effect on SCN3A function (BP4_moderate). This variant resides within a region of SCN3A that is defined as a mutational hotspot by the ClinGen sodium channel VCEP (PM1). Although there are both pathogenic and benign types of evidence for this variant, the high frequency of this variant in gnomAD strongly supports a benign classification, and the only evidence in support of pathogenicity is based on a prediction that this variant may lie in a mutational hotspot. In summary, this variant meets the criteria to be classified as Benign for autosomal dominant developmental and epileptic encephalopathy based on ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BA1, BP4, and PM1. (VCEP specifications version 1; 6/27/2023). -

not provided

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SCN3A-related disorder

Benign:1

Feb 27, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;.;.;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.79

T;T;T;T

MetaRNN

Benign

0.0089

T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.1

M;M;.;.

PhyloP100

2.7

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.4

D;D;.;D

REVEL

Benign

0.11

Sift

Uncertain

0.022

D;D;.;D

Sift4G

Benign

0.093

T;T;.;T

Polyphen

0.085, 0.0040

.;B;.;B

Vest4

0.23

MVP

0.67

MPC

1.6

ClinPred

0.12

GERP RS

6.2

Varity_R

0.21

gMVP

0.85

Mutation Taster

=78/22

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

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