rs140990288

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1BP4

This summary comes from the ClinGen Evidence Repository: The c.3250G>A variant in SCN3A is a missense variant predicted to cause the subsitution of valine by isoleucine at amino acid 1084 (p.Val1084Ile). The variant is present in 0.5% of the total population, and 0.7% of the European (non-Finnish) population, in gnomAD v2.1.1, which exceeds the threshold of 0.01% for BA1. The in silico predictor REVEL score for this variant is 0.155 which meets the criteria for BP4_Moderate. The variant has not been reported in an individual with developmental and epileptic encepathalopathy in the reported literature to date, and does not fall within a pathogenic enriched region. In summary, this variant meets the criteria to be classified as benign for autosomal dominant developmental and epileptic encephalopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BA1, BP4_Moderate (specification v1.0; approved 6/27/23). LINK:https://erepo.genome.network/evrepo/ui/classification/CA214587/MONDO:0100062/069

Frequency

Genomes: 𝑓 0.0051 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0078 ( 68 hom. )

Consequence

SCN3A
NM_006922.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:8

Conservation

PhyloP100: 0.0730

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 links:

ENSG00000236283 (HGNC:):

ENSG00000236283 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

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.3250G>A	p.Val1084Ile	missense_variant	Exon 18 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.3250G>A	p.Val1084Ile	missense_variant	Exon 18 of 28	1	NM_006922.4	ENSP00000283254.7		Q9NY46-3

Frequencies

GnomAD3 genomes

AF:

0.00515

AC:

783

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.00465

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00858

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00514

AC:

1293

AN:

251398

AF XY:

0.00526

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00544

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00217

Gnomad NFE exome

AF:

0.00731

Gnomad OTH exome

AF:

0.00702

GnomAD4 exome

AF:

0.00783

AC:

11441

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00766

AC XY:

5574

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00116

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.00548

AC:

245

AN:

44724

Gnomad4 ASJ exome

AF:

0.000153

AC:

AN:

26132

Gnomad4 EAS exome

AF:

0.0000252

AC:

AN:

39688

Gnomad4 SAS exome

AF:

0.00540

AC:

466

AN:

86258

Gnomad4 FIN exome

AF:

0.00202

AC:

108

AN:

53420

Gnomad4 NFE exome

AF:

0.00921

AC:

10238

AN:

1111976

Gnomad4 Remaining exome

AF:

0.00517

AC:

312

AN:

60394

Heterozygous variant carriers

629

1257

1886

2514

3143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

410

820

1230

1640

2050

<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:

0.00514

AC:

783

AN:

152270

Hom.:

Cov.:

AF XY:

0.00488

AC XY:

363

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00161

AC:

0.00161259

AN:

0.00161259

Gnomad4 AMR

AF:

0.00464

AC:

0.00464052

AN:

0.00464052

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00414

AC:

0.00414422

AN:

0.00414422

Gnomad4 FIN

AF:

0.00141

AC:

0.00141376

AN:

0.00141376

Gnomad4 NFE

AF:

0.00859

AC:

0.00858571

AN:

0.00858571

Gnomad4 OTH

AF:

0.00427

AC:

0.0042654

AN:

0.0042654

Heterozygous variant carriers

117

156

195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.00678

Hom.:

Bravo

AF:

0.00522

TwinsUK

AF:

0.0121

AC:

ALSPAC

AF:

0.0112

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00791

AC:

ExAC

AF:

0.00550

AC:

668

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00720

EpiControl

AF:

0.00640

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Nov 06, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 16, 2014

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 22, 2024

Athena Diagnostics

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

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SCN3A: BP4, BS1, BS2 -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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.3250G>A variant in SCN3A is a missense variant predicted to cause the subsitution of valine by isoleucine at amino acid 1084 (p.Val1084Ile). The variant is present in 0.5% of the total population, and 0.7% of the European (non-Finnish) population, in gnomAD v2.1.1, which exceeds the threshold of 0.01% for BA1. The in silico predictor REVEL score for this variant is 0.155 which meets the criteria for BP4_Moderate. The variant has not been reported in an individual with developmental and epileptic encepathalopathy in the reported literature to date, and does not fall within a pathogenic enriched region. In summary, this variant meets the criteria to be classified as benign for autosomal dominant developmental and epileptic encephalopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BA1, BP4_Moderate (specification v1.0; approved 6/27/23). -

Epilepsy, familial focal, with variable foci 4;C4693699:Developmental and epileptic encephalopathy, 62

Benign:1

Apr 22, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.29

DEOGEN2

Benign

0.25

T;.;.;.;.

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.78

T;T;T;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.0054

T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.4

N;N;.;.;.

PrimateAI

Benign

0.42

PROVEAN

Benign

0.19

N;N;.;N;N

REVEL

Benign

0.15

Sift

Benign

0.96

T;T;.;T;T

Sift4G

Benign

0.83

T;T;.;T;T

Polyphen

0.0060

B;B;.;B;B

Vest4

0.050

MVP

0.26

MPC

0.55

ClinPred

0.0013

GERP RS

4.1

Varity_R

0.017

gMVP

0.33

Mutation Taster

=97/3

polymorphism

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

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