rs140990288

Positions:

chr2-165127774-C-T

Variant summary

Our verdict is Benign. Variant got -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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
SCN3A	NM_006922.4 linkuse as main transcript	c.3250G>A	p.Val1084Ile	missense_variant	18/28	ENST00000283254.12	NP_008853.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN3A	ENST00000283254.12 linkuse as main transcript	c.3250G>A	p.Val1084Ile	missense_variant	18/28	1	NM_006922.4	ENSP00000283254	P1	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

GnomAD3 exomes

AF:

0.00514

AC:

1293

AN:

251398

Hom.:

AF XY:

0.00526

AC XY:

715

AN XY:

135870

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 SAS exome

AF:

0.00542

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

Gnomad4 AMR exome

AF:

0.00548

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00540

Gnomad4 FIN exome

AF:

0.00202

Gnomad4 NFE exome

AF:

0.00921

Gnomad4 OTH exome

AF:

0.00517

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

Gnomad4 AMR

AF:

0.00464

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00414

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00859

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00704

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 provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SCN3A: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 04, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 06, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 16, 2014	- -

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel, Clingen

May 09, 2024

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 22, 2022

- -

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;.;.;.

MutationTaster

Benign

1.0

N;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

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