rs41265137

Positions:

Variant summary

Our verdict is Benign. Variant got -6 ACMG points: 2P and 8B. BA1PP3_Moderate

This summary comes from the ClinGen Evidence Repository: The c.5584G>T variant in SCN3A is a missense variant predicted to case the substitution of glycine by cysteine at amino acid 1862 (p.Gly1862Cys). The highest population minor allele frequency in gnomAD v.2 is 8.2% (2915/35374 alleles) in the Latino population, which is higher than the ClinGen Epilepsy Sodium Channel threshold (0.3%) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.808 (PP3_Moderate). 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 computational predictor that should not override the high population frequency, which precludes this variant from being pathogenic for a rare disease. 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 and PP3_Moderate. (VCEP specifications version 1; 6/27/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA1938381/MONDO:0100062/069

Frequency

Genomes: 𝑓 0.014 ( 35 hom., cov: 32)

Exomes 𝑓: 0.016 ( 346 hom. )

Consequence

SCN3A
ENST00000283254.12 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:4

Conservation

PhyloP100: 7.91

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 -6 ACMG points.

PP3

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.5584G>T	p.Gly1862Cys	missense_variant	28/28	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.5584G>T	p.Gly1862Cys	missense_variant	28/28	1	NM_006922.4	ENSP00000283254	P1	Q9NY46-3
	ENST00000638199.1 linkuse as main transcript	n.1144-551C>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0137

AC:

2082

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00372

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0421

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00998

Gnomad FIN

AF:

0.0152

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0153

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.0213

AC:

5361

AN:

251160

Hom.:

147

AF XY:

0.0193

AC XY:

2619

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.00277

Gnomad AMR exome

AF:

0.0828

Gnomad ASJ exome

AF:

0.00357

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00892

Gnomad FIN exome

AF:

0.0142

Gnomad NFE exome

AF:

0.0151

Gnomad OTH exome

AF:

0.0197

GnomAD4 exome

AF:

0.0156

AC:

22806

AN:

1461804

Hom.:

346

Cov.:

AF XY:

0.0151

AC XY:

11016

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00248

Gnomad4 AMR exome

AF:

0.0838

Gnomad4 ASJ exome

AF:

0.00352

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.00975

Gnomad4 FIN exome

AF:

0.0162

Gnomad4 NFE exome

AF:

0.0147

Gnomad4 OTH exome

AF:

0.0136

GnomAD4 genome

AF:

0.0138

AC:

2096

AN:

152134

Hom.:

Cov.:

AF XY:

0.0136

AC XY:

1012

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00371

Gnomad4 AMR

AF:

0.0431

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.00978

Gnomad4 FIN

AF:

0.0152

Gnomad4 NFE

AF:

0.0153

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.0131

Hom.:

Bravo

AF:

0.0161

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.0163

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0147

AC:

126

ExAC

AF:

0.0190

AC:

2301

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.0135

EpiControl

AF:

0.0137

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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.5584G>T variant in SCN3A is a missense variant predicted to case the substitution of glycine by cysteine at amino acid 1862 (p.Gly1862Cys). The highest population minor allele frequency in gnomAD v.2 is 8.2% (2915/35374 alleles) in the Latino population, which is higher than the ClinGen Epilepsy Sodium Channel threshold (0.3%) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.808 (PP3_Moderate). 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 computational predictor that should not override the high population frequency, which precludes this variant from being pathogenic for a rare disease. 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 and PP3_Moderate. (VCEP specifications version 1; 6/27/2023). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

D;.;.;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.79

T;T;T;T

MetaRNN

Benign

0.0061

T;T;T;T

MetaSVM

Uncertain

0.31

MutationAssessor

Pathogenic

3.7

H;H;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-8.3

D;D;.;D

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0030

D;D;.;D

Sift4G

Pathogenic

0.0

D;D;.;D

Polyphen

1.0

.;D;.;D

Vest4

0.66

MPC

1.8

ClinPred

0.071

GERP RS

5.9

Varity_R

0.73

gMVP

0.98

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