2-166286383-C-T

Variant names:

• chr2-166286383-C-T
• rs187453572
• NM_001365536.1:c.1555G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001365536.1(SCN9A):​c.1555G>A​(p.Glu519Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000954 in 1,613,682 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00061 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (1 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:5
• Conservation: PhyloP100: 4.53
• Publications: 13 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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08226916).
• BP6: Variant 2-166286383-C-T is Benign according to our data. Variant chr2-166286383-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193859.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.1555G>A	p.Glu519Lys	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.1555G>A	p.Glu519Lys	missense_variant	Exon 11 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.1555G>A	p.Glu519Lys	missense_variant	Exon 11 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.1555G>A	p.Glu519Lys	missense_variant	Exon 11 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.1555G>A	p.Glu519Lys	missense_variant	Exon 11 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.1555G>A	p.Glu519Lys	missense_variant	Exon 11 of 15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000450 AC: 112 AN: 248934 AF XY: 0.000504

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000841

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000989 AC: 1446 AN: 1461406 Hom.: 1 Cov.: 31 AF XY: 0.000971 AC XY: 706 AN XY: 726960

African (AFR) AF: 0.000120 AC: 4 AN: 33450

American (AMR) AF: 0.000201 AC: 9 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26122

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86126

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53392

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00124 AC: 1376 AN: 1111782

Other (OTH) AF: 0.000646 AC: 39 AN: 60368

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74452

African (AFR) AF: 0.000193 AC: 8 AN: 41554

American (AMR) AF: 0.000588 AC: 9 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00103 AC: 70 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000702 Hom.: 1

Bravo AF: 0.000627

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000259 AC: 1

ESP6500EA AF: 0.00121 AC: 10

ExAC AF: 0.000430 AC: 52

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.000949

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:7

May 17, 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.1555G>A; p.Glu519Lys variant (rs187453572) is reported in the literature in one individual with febrile seizures and in several individuals with small fiber neuropathy (Almomani 2023, Eijkenboom 2019, Singh 2009). This variant is also reported in ClinVar (Variation ID: 193859) and is found in the non-Finnish European population with an allele frequency of 0.09% (111/128,350 alleles, including one homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.549). Due to limited information, the clinical significance of the p.Glu519Lys variant is uncertain at this time. References: Almomani R et al. Genetic Profiling of Sodium Channels in Diabetic Painful and Painless and Idiopathic Painful and Painless Neuropathies. Int J Mol Sci. 2023 May 5;24(9):8278. PMID: 37175987. 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. Singh NA et al. A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome. PLoS Genet. 2009 Sep;5(9):e1000649. PMID: 19763161. -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 09, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 08, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed as a heterozygous variant in patients with Dravet syndrome or diabetic peripheral neuropathy (PMID: 19763161, 37175987). Also observed with another variant in the SCN9A gene in a patient with small fiber neuropathy in published literature (PMID: 30554136); however, it is unknown if the variants are on the same allele (in cis) or on opposite alleles (in trans); Reported previously as a variant of uncertain significance in a patient with CMT1; however, no further clinical or segregation information was provided (PMID: 26392352); Reported previously in a control sample and not seen in case samples from patients with Rolandic epilepsy (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: 28488083, 37175987, 30554136, 37195288, 19763161, 32601768, 29358611, 26392352, 29264398) -

Oct 14, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 11, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 07, 2024

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Mar 26, 2025

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.1555G>A (p.Glu519Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00045 in 248934 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in SCN9A causing Channelopathy-Associated Congenital Insensitivity To Pain, Autosomal Recessive (0.00045 vs 0.0011), allowing no conclusion about variant significance. c.1555G>A has been reported in the literature in one individual affected with Dravet syndrome, without strong evidence for causality (Singh_2009). These report(s) do not provide unequivocal conclusions about association of the variant with Channelopathy-Associated Congenital Insensitivity To Pain, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 19763161). ClinVar contains an entry for this variant (Variation ID: 193859). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Uncertain:1

Dec 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E519K variant (also known as c.1555G>A), located in coding exon 10 of the SCN9A gene, results from a G to A substitution at nucleotide position 1555. The glutamic acid at codon 519 is replaced by lysine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant is unlikely to be causative of primary erythermalgia/small fiber neuropathy, and paroxysmal extreme pain disorder; however, its contribution to the development of congenital insensitivity to pain and hereditary sensory autonomic neuropathy type II is uncertain. -

Generalized epilepsy with febrile seizures plus, type 7 Uncertain:1

Jul 11, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Seizure Uncertain:1

Aug 25, 2017

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Primary erythromelalgia 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. -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive 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. -

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

Jan 29, 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

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	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	.;T;.;.;T;.;.
Eigen	Benign	0.088
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.72	T;.;T;T;T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.082	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.3	M;M;M;.;M;M;.
PhyloP100		4.5
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.1	N;.;.;.;.;N;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.012	D;.;.;.;.;D;.
Sift4G	Benign	0.49	T;T;.;.;.;T;.
Polyphen		0.38	.;B;.;.;B;.;.
Vest4		0.45
MVP		0.81
MPC		0.18
ClinPred		0.067	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.41
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs187453572; hg19: chr2-167142893; COSMIC: COSV57603001; COSMIC: COSV57603001;