NM_006922.4:c.3250G>A

Variant names:

• chr2-165127774-C-T
• rs140990288
• NM_006922.4:c.3250G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1 BP4

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
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: 0.0730

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]

ENSG00000236283 (HGNC:):

ACMG classification

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 rank	MANE	Protein	UniProt
SCN3A	NM_006922.4	c.3250G>A	p.Val1084Ile	missense_variant	Exon 18 of 28	ENST00000283254.12	NP_008853.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN3A	ENST00000283254.12	c.3250G>A	p.Val1084Ile	missense_variant	Exon 18 of 28	1	NM_006922.4	ENSP00000283254.7

Frequencies

GnomAD3 genomes AF: 0.00515 AC: 783 AN: 152152 Hom.: 3 Cov.: 32

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.: 9 AF XY: 0.00526 AC XY: 715 AN XY: 135870

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.: 68 Cov.: 32 AF XY: 0.00766 AC XY: 5574 AN XY: 727226

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.: 3 Cov.: 32 AF XY: 0.00488 AC XY: 363 AN XY: 74444

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.: 7

Bravo AF: 0.00522

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00791 AC: 68

ExAC AF: 0.00550 AC: 668

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00720

EpiControl AF: 0.00640

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Apr 22, 2024

Athena Diagnostics

Significance: 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

- -

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

- -

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN3A: BP4, BS1, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Early infantile epileptic encephalopathy with suppression bursts 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	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Benign	0.29
DEOGEN2	Benign	0.25	T;.;.;.;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.78	T;T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0054	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.4	N;N;.;.;.
PrimateAI	Benign	0.42	T
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	T
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

Other links and lift over

dbSNP: rs140990288; hg19: chr2-165984284; COSMIC: COSV51826961;