2-165090569-C-A

Variant names:

• chr2-165090569-C-A
• rs41265137
• NM_006922.4:c.5584G>T

Variant summary

Our verdict is Benign. The variant received -6 ACMG points: 2P and 8B. BA1 PP3_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 NM_006922.4 missense
• Clinical Significance: Benign reviewed by expert panel B:4
• Conservation: PhyloP100: 7.91

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
SCN3A	NM_006922.4	c.5584G>T	p.Gly1862Cys	missense_variant	Exon 28 of 28	ENST00000283254.12	NP_008853.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN3A	ENST00000283254.12	c.5584G>T	p.Gly1862Cys	missense_variant	Exon 28 of 28	1	NM_006922.4	ENSP00000283254.7

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2082 AN: 152016 Hom.: 31 Cov.: 32

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

GnomAD2 exomes AF: 0.0213 AC: 5361 AN: 251160 AF XY: 0.0193

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 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.: 32 AF XY: 0.0151 AC XY: 11016 AN XY: 727202

Gnomad4 AFR exome AF: 0.00248 AC: 83 AN: 33470

Gnomad4 AMR exome AF: 0.0838 AC: 3745 AN: 44692

Gnomad4 ASJ exome AF: 0.00352 AC: 92 AN: 26134

Gnomad4 EAS exome AF: 0.000277 AC: 11 AN: 39700

Gnomad4 SAS exome AF: 0.00975 AC: 841 AN: 86258

Gnomad4 FIN exome AF: 0.0162 AC: 865 AN: 53414

Gnomad4 NFE exome AF: 0.0147 AC: 16305 AN: 1111974

Gnomad4 Remaining exome AF: 0.0136 AC: 824 AN: 60394

GnomAD4 genome AF: 0.0138 AC: 2096 AN: 152134 Hom.: 35 Cov.: 32 AF XY: 0.0136 AC XY: 1012 AN XY: 74360

Gnomad4 AFR AF: 0.00371 AC: 0.00371084 AN: 0.00371084

Gnomad4 AMR AF: 0.0431 AC: 0.043065 AN: 0.043065

Gnomad4 ASJ AF: 0.00202 AC: 0.00201613 AN: 0.00201613

Gnomad4 EAS AF: 0.00116 AC: 0.00116369 AN: 0.00116369

Gnomad4 SAS AF: 0.00978 AC: 0.00977537 AN: 0.00977537

Gnomad4 FIN AF: 0.0152 AC: 0.0151801 AN: 0.0151801

Gnomad4 NFE AF: 0.0153 AC: 0.0152901 AN: 0.0152901

Gnomad4 OTH AF: 0.0104 AC: 0.0104167 AN: 0.0104167

Alfa AF: 0.0138 Hom.: 28

Bravo AF: 0.0161

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0163 AC: 63

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0147 AC: 126

ExAC AF: 0.0190 AC: 2301

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.0135

EpiControl AF: 0.0137

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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.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	T
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T;T;T;T
MetaRNN	Benign	0.0061	T;T;T;T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	3.7	H;H;.;.
PrimateAI	Pathogenic	0.89	D
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	T
GERP RS		5.9
Varity_R		0.73
gMVP		0.98
Mutation Taster		=85/15	polymorphism (auto)

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: rs41265137; hg19: chr2-165947079;