rs58022607

Positions:

chr2-166286469-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001365536.1(SCN9A):c.1469G>A(p.Ser490Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,613,832 control chromosomes in the GnomAD database, including 758 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.041 ( 389 hom., cov: 31)

Exomes 𝑓: 0.0078 ( 369 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.386

Variant links:

Genes affected

SCN9A (HGNC:10597): (sodium voltage-gated channel alpha subunit 9) This gene encodes a voltage-gated sodium channel which plays a significant role in nociception signaling. Mutations in this gene have been associated with primary erythermalgia, channelopathy-associated insensitivity to pain, and paroxysmal extreme pain disorder. [provided by RefSeq, Aug 2009]

SCN9A links:

SCN1A-AS1 (HGNC:):

SCN1A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016465783).

BP6

Variant 2-166286469-C-T is Benign according to our data. Variant chr2-166286469-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 130258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166286469-C-T is described in Lovd as [Benign]. Variant chr2-166286469-C-T is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1 linkuse as main transcript	c.1469G>A	p.Ser490Asn	missense_variant	11/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN9A	ENST00000642356.2 linkuse as main transcript	c.1469G>A	p.Ser490Asn	missense_variant	11/27		NM_001365536.1	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11 linkuse as main transcript	c.1469G>A	p.Ser490Asn	missense_variant	11/27	5		ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5 linkuse as main transcript	c.1469G>A	p.Ser490Asn	missense_variant	11/27	5		ENSP00000386306.1	Q15858-3
SCN9A	ENST00000645907.1 linkuse as main transcript	c.1469G>A	p.Ser490Asn	missense_variant	11/27			ENSP00000495983.1	Q15858-4
SCN9A	ENST00000454569.6 linkuse as main transcript	c.1469G>A	p.Ser490Asn	missense_variant	11/15	1		ENSP00000413212.2	A0A0C4DG82

Frequencies

GnomAD3 genomes

AF:

0.0412

AC:

6264

AN:

152116

Hom.:

389

Cov.:

show subpopulations

Gnomad AFR

AF:

0.132

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0200

Gnomad ASJ

AF:

0.0282

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0160

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00353

Gnomad OTH

AF:

0.0349

GnomAD3 exomes

AF:

0.0152

AC:

3780

AN:

249102

Hom.:

172

AF XY:

0.0140

AC XY:

1889

AN XY:

135136

show subpopulations

Gnomad AFR exome

AF:

0.136

Gnomad AMR exome

AF:

0.00849

Gnomad ASJ exome

AF:

0.0358

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.0171

Gnomad FIN exome

AF:

0.0000928

Gnomad NFE exome

AF:

0.00368

Gnomad OTH exome

AF:

0.0137

GnomAD4 exome

AF:

0.00775

AC:

11334

AN:

1461598

Hom.:

369

Cov.:

AF XY:

0.00789

AC XY:

5734

AN XY:

727074

show subpopulations

Gnomad4 AFR exome

AF:

0.136

Gnomad4 AMR exome

AF:

0.0102

Gnomad4 ASJ exome

AF:

0.0369

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0173

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.00245

Gnomad4 OTH exome

AF:

0.0162

GnomAD4 genome

AF:

0.0413

AC:

6287

AN:

152234

Hom.:

389

Cov.:

AF XY:

0.0398

AC XY:

2964

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.132

Gnomad4 AMR

AF:

0.0201

Gnomad4 ASJ

AF:

0.0282

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.0164

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00353

Gnomad4 OTH

AF:

0.0346

Alfa

AF:

0.0111

Hom.:

Bravo

AF:

0.0455

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.125

AC:

464

ESP6500EA

AF:

0.00538

AC:

ExAC

AF:

0.0169

AC:

2039

Asia WGS

AF:

0.0130

AC:

AN:

3476

EpiCase

AF:

0.00540

EpiControl

AF:

0.00682

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 22, 2014	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 19763161, 27884173) -

Primary erythromelalgia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Small fiber neuropathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Paroxysmal extreme pain disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.23

.;T;.;.;T;.;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.042

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.71

T;.;T;T;T;T;T

MetaRNN

Benign

0.0016

T;T;T;T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.69

N;N;N;.;N;N;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.48

N;N;.;.;.;N;.

REVEL

Benign

0.23

Sift

Benign

0.24

T;D;.;.;.;T;.

Sift4G

Benign

0.41

T;T;.;.;.;T;.

Polyphen

0.0

.;B;.;.;B;.;.

Vest4

0.060

MPC

0.11

ClinPred

0.0048

GERP RS

4.0

Varity_R

0.053

gMVP

0.27

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