rs199692186

Variant names:

• chr2-166272748-T-C
• rs199692186
• NM_001365536.1:c.3002A>G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001365536.1(SCN9A):​c.3002A>G​(p.Tyr1001Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000704 in 1,561,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00072 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:10 B:7
• Conservation: PhyloP100: 1.83

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01835671).
• BP6: Variant 2-166272748-T-C is Benign according to our data. Variant chr2-166272748-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130260.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=2, Uncertain_significance=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.3002A>G	p.Tyr1001Cys	missense_variant	Exon 17 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.3002A>G	p.Tyr1001Cys	missense_variant	Exon 17 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.3002A>G	p.Tyr1001Cys	missense_variant	Exon 17 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.2969A>G	p.Tyr990Cys	missense_variant	Exon 17 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.2969A>G	p.Tyr990Cys	missense_variant	Exon 17 of 27			ENSP00000495983.1

Frequencies

GnomAD3 genomes AF: 0.000547 AC: 83 AN: 151856 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000634 AC: 130 AN: 205034 Hom.: 0 AF XY: 0.000590 AC XY: 65 AN XY: 110138

Gnomad AFR exome AF: 0.000135

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00513

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000499

Gnomad FIN exome AF: 0.000266

Gnomad NFE exome AF: 0.000856

Gnomad OTH exome AF: 0.00127

GnomAD4 exome AF: 0.000721 AC: 1016 AN: 1409424 Hom.: 0 Cov.: 31 AF XY: 0.000731 AC XY: 509 AN XY: 696032

Gnomad4 AFR exome AF: 0.000159

Gnomad4 AMR exome AF: 0.0000840

Gnomad4 ASJ exome AF: 0.00458

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000921

Gnomad4 FIN exome AF: 0.000175

Gnomad4 NFE exome AF: 0.000788

Gnomad4 OTH exome AF: 0.000500

GnomAD4 genome AF: 0.000547 AC: 83 AN: 151856 Hom.: 0 Cov.: 31 AF XY: 0.000553 AC XY: 41 AN XY: 74100

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.000480

Alfa AF: 0.000965 Hom.: 0

Bravo AF: 0.000620

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000276 AC: 1

ESP6500EA AF: 0.00111 AC: 9

ExAC AF: 0.000580 AC: 70

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:10 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:8 Benign:1

-

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 13, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in two individuals with Rolandic epilepsy in published literature; however, no additional information was provided (PMID: 29358611); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29358611, 30554136) -

-

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN9A: BP4 -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SCN9A p.Tyr990Cys variant was identified in 3 of 3192 proband chromosomes (frequency: 0.00094; one compound heterozygote and two heterozygotes) from individuals with peripheral neuropathy (Wadhawan_2017_PMID_29264398; Eijkenboom_2018_PMID_30554136). The variant was identified in dbSNP (ID: rs199692186) and ClinVar (classified as likely benign by PreventionGenetics, Invitae and Illumina, and as uncertain significance by GeneDx, EGL Genetic Diagnostics and Genetic Services Laboratory, University of Chicago, and classified as pathogenic by Bioinformatics Core Luxembourg Center for Systems Biomedicine). The variant was identified in control databases in 143 of 236408 chromosomes at a frequency of 0.0006049 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 35 of 6532 chromosomes (freq: 0.005358), Other in 7 of 5826 chromosomes (freq: 0.001202), European (non-Finnish) in 92 of 113582 chromosomes (freq: 0.00081), European (Finnish) in 5 of 22294 chromosomes (freq: 0.000224), African in 3 of 23534 chromosomes (freq: 0.000128) and South Asian in 1 of 20024 chromosomes (freq: 0.00005), but was not observed in the Latino or East Asian populations. The p.Tyr990 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Aug 27, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SCN9A c.2969A>G; p.Tyr990Cys variant (rs199692186) is reported in the literature in an individual with small fiber neuropathy however clear disease association was not provided (Eijkenboom 2019), and has also been found in an epilepsy cohort in a case and a control (Bobbili 2018). This variant is reported in ClinVar (Variation ID: 130260). This variant is found in the general population with an overall allele frequency of 0.06% (143/236,408 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.493). While the p.Tyr990Cys variant is likely excluded as a pathogenic dominant allele due to the high population frequency, recessive effects of this variant cannot be ruled out. The clinical significance of this variant is uncertain at this time. References: Bobbili DR et al. Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy. Eur J Hum Genet. 2018 Feb;26(2):258-264. PMID: 29358611. Eijkenboom I et al. Yield of peripheral sodium channels gene screening in pure small fibre neuropathy. J Neurol Neurosurg Psychiatry. 2019 Mar;90(3):342-352. PMID: 30554136. -

Nov 03, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 12, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary erythromelalgia Uncertain:1 Benign:1

Apr 10, 2024

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (A>G) at position 3002 of the coding sequence of the SCN9A gene that results in a tyrosine to cysteine amino acid change at residue 1001 of the sodium voltage-gated channel alpha subunit 9 protein. The 1001 residue falls in the cytoplasmic domain between domains II and III (PMID: 20635406). This is a previously reported variant (ClinVar 130260) that has been observed in individuals affected by small fiber neuropathy or Rolandic epilepsy (PMID: 30554136, 37079850, 29358611). In addition, this variant has a been observed in unaffected control cohorts (PMID: 29358611). This variant is present in 213 of 356890 alleles (0.0597%) in the gnomAD population dataset. The frequent observation of this variant in a control population may be the result of incomplete penetrance (PMID: 37079850). Multiple bioinformatic tools provide conflicting predictions concerning the impact of this variant, though this residue is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. Based upon the evidence, we consider this a variant of uncertain significance. ACMG Criteria: -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Self-limited epilepsy with centrotemporal spikes Pathogenic:1

Jan 01, 2017

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

CAADphred>15 -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Sep 29, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Small fiber neuropathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paroxysmal extreme pain disorder Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	.;D;.;.;D;.
Eigen	Benign	0.024
Eigen_PC	Benign	0.057
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.81	T;.;T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.018	T;T;T;T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.5	.;M;.;.;M;M
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-5.7	D;.;.;.;.;D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D;.;.;.;.;D
Sift4G	Uncertain	0.052	T;T;.;.;.;T
Vest4		0.72
MVP		0.73
MPC		0.62
ClinPred		0.13	T
GERP RS		5.4
Varity_R		0.53
gMVP		0.54

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: rs199692186; hg19: chr2-167129258; COSMIC: COSV99069747; COSMIC: COSV99069747;