2-166280508-A-T

Variant names:

• chr2-166280508-A-T
• rs200945460
• NM_001365536.1:c.2192T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001365536.1(SCN9A):​c.2192T>A​(p.Ile731Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000257 in 1,589,396 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I731T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:9 B:6
• Conservation: PhyloP100: 7.39
• Publications: 9 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20788541).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.2192T>A	p.Ile731Lys	missense_variant	Exon 14 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.2192T>A	p.Ile731Lys	missense_variant	Exon 14 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.2192T>A	p.Ile731Lys	missense_variant	Exon 14 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.2159T>A	p.Ile720Lys	missense_variant	Exon 14 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.2159T>A	p.Ile720Lys	missense_variant	Exon 14 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.2159T>A	p.Ile720Lys	missense_variant	Exon 14 of 15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000156 AC: 33 AN: 212026 AF XY: 0.000114

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000357

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.000926

GnomAD4 exome AF: 0.000263 AC: 378 AN: 1437076 Hom.: 0 Cov.: 31 AF XY: 0.000244 AC XY: 174 AN XY: 712282

African (AFR) AF: 0.0000904 AC: 3 AN: 33170

American (AMR) AF: 0.000504 AC: 21 AN: 41650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25542

East Asian (EAS) AF: 0.00 AC: 0 AN: 39106

South Asian (SAS) AF: 0.00 AC: 0 AN: 82802

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51928

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5726

European-Non Finnish (NFE) AF: 0.000308 AC: 338 AN: 1097736

Other (OTH) AF: 0.000219 AC: 13 AN: 59416

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74482

African (AFR) AF: 0.0000722 AC: 3 AN: 41574

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000318 Hom.: 0

Bravo AF: 0.000351

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000245 AC: 2

ExAC AF: 0.0000998 AC: 12

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:9 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary erythromelalgia Pathogenic:1 Uncertain:2 Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Dec 01, 2021

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 02, 2014

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as disease-causing and was found once in our laboratory in a 61-year-old female with Bell's palsy, Melkersson-Rosenthal syndrome, right-sided trigeminal neuralgia, fibromyalgia, hyperlipidemia, hyperglycemia, thunderclap headache, similarly affected mother and siblings (not tested). Additionally, this variant has been seen twice in younger individuals without related phenotypes (a 35-year-old female and a 14-year-old male). -

Jan 05, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:2 Benign:1

Apr 16, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 29, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SCN9A c.2159T>A (p.Ile720Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 212026 control chromosomes. This frequency does not allow conclusions about variant significance. c.2159T>A has been reported in the literature in individuals presenting with features of Small nerve fiber neuropathy (SFN), inherited erythromelalgia (IEM), Charcot-Marie-Tooth disease Type 2 (CMT2), Paroxysomal extreme pain disorder (PEPD) (example, Faber_2012, Goldberg_2012, Antoniadi_2015, Cannon_2016). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in impaired slow inactivation resulting in neuronal hyperexcitability due to increased number of action potentials resulting from an increase in the number of channels available for activation close to the resting potential of dorsal root ganglion (DRG) neurons (Faber_2012). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Likely benign, n=2; VUS, n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

May 04, 2022

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive Uncertain:2 Benign:1

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

-

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Small fiber neuropathy Pathogenic:1 Benign:1

Jan 01, 2012

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2

Jul 15, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in patients with small fiber neuropathy or Charcot-Marie-Tooth type 2, who did not have any other variants identified in the SCN9A gene (PMID: 25250524, 27525141, 26392352); Published functional studies demonstrate that I720K causes a gain of function by altering channel inactivation leading to hyperexcitability of the neurons (PMID: 21698661); 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: 22803682, 27525141, 23280954, 22035805, 26392352, 30672368, 33144682, 25250524, 21698661, Newton2025[Preprint], 26633545) -

May 18, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Nov 29, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I720K variant (also known as c.2159T>A), located in coding exon 13 of the SCN9A gene, results from a T to A substitution at nucleotide position 2159. The isoleucine at codon 720 is replaced by lysine, an amino acid with dissimilar properties. This alteration has been detected in the heterozygous state in multiple patients with adult-onset pain disorders (Cannon A et al. Case Rep Neurol Med, 2016 Jul;2016:9212369; Faber CG et al. Ann. Neurol., 2012 Jan;71:26-39; Goldberg YP et al. Pain, 2012 Jan;153:80-5). Expression of p.I720K in HEK293 cells showed impaired slow inactivation and caused DRG neurons to be hyperexcitable with a 43% reduction in current threshold (Faber CG et al. Ann. Neurol., 2012 Jan;71:26-39). However, given the population frequency of this alteration based on data from the Genome Aggregation Database (gnomAD), it is considered unlikely to cause dominant disease. Its pathogenicity for recessive disease remains unknown. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of primary erythermalgia/small fiber neuropathy and paroxysmal extreme pain disorder (PEPD), ; however, its contribution to the development of congenital insensitivity to pain (CIP) and hereditary sensory autonomic neuropathy type II (HSAN2D) is uncertain. -

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

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paroxysmal extreme pain disorder Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Uncertain	0.58	.;D;.;.;D;.;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;.;T;D;T;T;D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.7	.;L;.;.;L;L;.
PhyloP100		7.4
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.5	D;.;.;.;.;D;.
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;.;.;.;.;D;.
Sift4G	Benign	0.14	T;T;.;.;.;T;.
Vest4		0.59
MVP		0.86
MPC		0.27
ClinPred		0.15	T
GERP RS		5.9
Varity_R		0.79
gMVP		0.56
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs200945460; hg19: chr2-167137018;