2-166286469-C-T

Variant names:

• chr2-166286469-C-T
• rs58022607
• NM_001365536.1:c.1469G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.386

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]

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

ACMG classification

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 rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.1469G>A	p.Ser490Asn	missense_variant	Exon 11 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.1469G>A	p.Ser490Asn	missense_variant	Exon 11 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.1469G>A	p.Ser490Asn	missense_variant	Exon 11 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.1469G>A	p.Ser490Asn	missense_variant	Exon 11 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.1469G>A	p.Ser490Asn	missense_variant	Exon 11 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.1469G>A	p.Ser490Asn	missense_variant	Exon 11 of 15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes AF: 0.0412 AC: 6264 AN: 152116 Hom.: 389 Cov.: 31

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

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.: 31 AF XY: 0.00789 AC XY: 5734 AN XY: 727074

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.: 31 AF XY: 0.0398 AC XY: 2964 AN XY: 74452

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.: 82

Bravo AF: 0.0455

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.125 AC: 464

ESP6500EA AF: 0.00538 AC: 44

ExAC AF: 0.0169 AC: 2039

Asia WGS AF: 0.0130 AC: 46 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

Submissions by phenotype

not specified Benign:7

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 22, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19763161, 27884173) -

Primary erythromelalgia Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Small fiber neuropathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paroxysmal extreme pain disorder Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.23	.;T;.;.;T;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.042
FATHMM_MKL	Benign	0.65	D
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	T
MutationAssessor	Benign	0.69	N;N;N;.;N;N;.
PrimateAI	Benign	0.33	T
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	T
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

Other links and lift over

dbSNP: rs58022607; hg19: chr2-167142979; COSMIC: COSV104409075; COSMIC: COSV104409075;