rs3731762

Positions:

chr2-165090746-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 made for transcript

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
SCN3A	NM_006922.4 linkuse as main transcript	c.5407G>A	p.Asp1803Asn	missense_variant	28/28	ENST00000283254.12	NP_008853.3	Q9NY46-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN3A	ENST00000283254.12 linkuse as main transcript	c.5407G>A	p.Asp1803Asn	missense_variant	28/28	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

GnomAD3 exomes

AF:

0.00137

AC:

344

AN:

251408

Hom.:

AF XY:

0.00128

AC XY:

174

AN XY:

135878

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 SAS exome

AF:

0.00134

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0168

Gnomad4 SAS exome

AF:

0.00103

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000611

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0153

Gnomad4 SAS

AF:

0.00229

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000162

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

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.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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2024

- -

SCN3A-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 2024

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

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;.;.

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

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