2-166280508-A-T

Position:

chr2-166280508-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_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).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:9B:6

Conservation

PhyloP100: 7.39

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:54069): (SCN1A and SCN9A antisense RNA 1)

SCN1A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1 link	c.2192T>A	p.Ile731Lys	missense_variant	14/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN9A	ENST00000642356.2 link	c.2192T>A	p.Ile731Lys	missense_variant	14/27		NM_001365536.1	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11 link	c.2192T>A	p.Ile731Lys	missense_variant	14/27	5		ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5 link	c.2159T>A	p.Ile720Lys	missense_variant	14/27	5		ENSP00000386306.1	Q15858-3
SCN9A	ENST00000645907.1 link	c.2159T>A	p.Ile720Lys	missense_variant	14/27			ENSP00000495983.1	Q15858-4
SCN9A	ENST00000454569.6 link	c.2159T>A	p.Ile720Lys	missense_variant	14/15	1		ENSP00000413212.2	A0A0C4DG82

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000156

AC:

AN:

212026

Hom.:

AF XY:

0.000114

AC XY:

AN XY:

113744

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.000244

AC XY:

174

AN XY:

712282

show subpopulations

Gnomad4 AFR exome

AF:

0.0000904

Gnomad4 AMR exome

AF:

0.000504

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000193

Gnomad4 NFE exome

AF:

0.000308

Gnomad4 OTH exome

AF:

0.000219

GnomAD4 genome

AF:

0.000197

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000318

Hom.:

Bravo

AF:

0.000351

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000245

AC:

ExAC

AF:

0.0000998

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary erythromelalgia

Pathogenic:1Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Dec 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Pathogenic, flagged submission	clinical testing	Baylor Genetics	May 02, 2014	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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jan 05, 2023	- -

not specified

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 16, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 29, 2022	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. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -

Small fiber neuropathy

Pathogenic:1Benign:1

Pathogenic, flagged submission	literature only	OMIM	Jan 01, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2024	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) -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2021

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Paroxysmal extreme pain disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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 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

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Uncertain

0.58

.;D;.;.;D;.;.

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

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

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.21

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

MetaSVM

Uncertain

0.53

MutationAssessor

Benign

1.7

.;L;.;.;L;L;.

PrimateAI

Uncertain

0.63

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

GERP RS

5.9

Varity_R

0.79

gMVP

0.56

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