chr2-166304242-G-C

Position:

chr2-166304242-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001365536.1(SCN9A):c.684C>G(p.Ile228Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,613,092 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 0.00078 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:17B:2

Conservation

PhyloP100: -1.00

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:

SCN9A (HGNC:):

SCN9A 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=0.093299).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1 linkuse as main transcript	c.684C>G	p.Ile228Met	missense_variant	6/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN9A	ENST00000642356.2 linkuse as main transcript	c.684C>G	p.Ile228Met	missense_variant	6/27		NM_001365536.1	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11 linkuse as main transcript	c.684C>G	p.Ile228Met	missense_variant	6/27	5		ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5 linkuse as main transcript	c.684C>G	p.Ile228Met	missense_variant	6/27	5		ENSP00000386306.1	Q15858-3
SCN9A	ENST00000454569.6 linkuse as main transcript	c.684C>G	p.Ile228Met	missense_variant	6/15	1		ENSP00000413212.2	A0A0C4DG82
SCN9A	ENST00000452182.2 linkuse as main transcript	c.684C>G	p.Ile228Met	missense_variant	7/11	1		ENSP00000393141.2	H7C064
SCN9A	ENST00000645907.1 linkuse as main transcript	c.597-120C>G		intron_variant				ENSP00000495983.1	Q15858-4

Frequencies

GnomAD3 genomes

AF:

0.000776

AC:

118

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000849

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00143

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000893

AC:

223

AN:

249660

Hom.:

AF XY:

0.000857

AC XY:

116

AN XY:

135396

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.0000871

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000925

Gnomad NFE exome

AF:

0.00172

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.00123

AC:

1791

AN:

1460884

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

862

AN XY:

726762

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000936

Gnomad4 NFE exome

AF:

0.00152

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.000775

AC:

118

AN:

152208

Hom.:

Cov.:

AF XY:

0.000672

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000849

Gnomad4 NFE

AF:

0.00143

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000989

Hom.:

Bravo

AF:

0.000676

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000964

AC:

117

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00131

EpiControl

AF:

0.00149

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:17Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 22, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 03, 2020	The p.Ile228Met variant (rs71428908) has been reported in association with at least four disease phenotypes, including Dravet syndrome, Charcot-Marie-Tooth type II, Erythermalgia, and small fiber neuropathy (Singh, 2009; Ylikallio, 2014; Namer, 2015; Faber, 2012). These studies do not demonstrate segregation of the variant with disease; however Estacion (2011) demonstrate hyperexcitability of dorsal root ganglia neurons that express the variant. In addition, Persson (2013) showed a 20 percent reduction in neurite length by expression the variant protein in cell culture. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.16 percent in the European Non-Finnish population (identified on 205 out of 126,370 chromosomes), and has been reported to the ClinVar database (Variation ID: 198153). The isoleucine at position 228 is highly conserved up to platypus considering 12 species (Alamut v2.10) and computational analyses of the p.Ile228Met variant on protein structure and function indicate a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Considering the overabundance of this variant in the general population, it is likely a polymorphism, however any role in disease can not be ruled out. Altogether, there is not enough evidence to classify the p.Ile228Met variant with certainty. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SCN9A: PM2:Supporting, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 24, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 24, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 03, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2024	Reported in the heterozygous state in a patient with biopsy-confirmed small fiber neuropathy (PMID: 21698661); Reported as a modifier for Dravet syndrome when observed in the heterozygous state along with a heterozygous pathogenic variant in a gene known to cause epilepsy, SCN1A; however, I228M was also identified in unaffected controls (PMID: 19763161); Published functional studies demonstrate a damaging effect in Zebrafish embryos over-expressing I228M, including decreased density of the small nerve fibers and increased activity induced by temperature change (PMID: 30316835); Published functional studies demonstrate a gain-of-function effect which alters the channel function (PMID: 22136189, 21698661); In vitro studies show I228M impairs the regeneration and/or degeneration of dorsal root ganglion neuron axons (PMID: 23280954); 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: 33892629, 31851560, 33323889, 29911575, 34426522, 22136189, 25993546, 26264438, 26949748, 2558527, 20440589, 37003485, 37175987, 21698661, 19763161, 30316835, 23280954, 39000354) -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 31, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 14, 2024	Variant summary: SCN9A c.684C>G (p.Ile228Met) results in a conservative amino acid change in the Ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00089 in 249660 control chromosomes, predominantly at a frequency of 0.0017 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN9A causing Channelopathy-Associated Congenital Insensitivity To Pain, Autosomal Recessive phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.684C>G has been reported in the literature in multiple individuals affected with small nerve fiber neuropathy, Pain syndrome, erythromelalgia (example, Faber_2012, Estacion_2011, Namer_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Channelopathy-Associated Congenital Insensitivity To Pain, Autosomal Recessive. Co-occurrences with other pathogenic variant(s) have been reported in one patient with Dravet syndrome (SCN1A c.2944G>C, p.V982L), providing supporting evidence for a benign role (Singh_2009). Mulitple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in DRG neuron hyperexcitability and minimal phenotypes in young I228M knockin mice, and loss-of-function changes in DRG including loss of sodium conductance, changes in activation and slow inactivation dynamics in aged I228M knockin mice, further, it was only in aged knockin mice that a profound insensitivity to noxious heat and cold, as well skin lesions that span the body are identified (Wimalasena_2023, Faber_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22136189, 21698661, 25993546, 19763161, 37003485). ClinVar contains an entry for this variant (Variation ID: 198153). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Primary erythromelalgia

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 30, 2018	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 09, 2022	Criteria applied: PS3, PP3 -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2022

Unlikely to be causative of SCN9A-related neuropathic pain syndromes (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Neuropathy, hereditary sensory and autonomic, type 2A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Mar 20, 2020

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PP3. -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 30, 2018

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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Primary erythromelalgia;C1833661:Paroxysmal extreme pain disorder;C1855739:Channelopathy-associated congenital insensitivity to pain, autosomal recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 21, 2024

- -

Primary erythromelalgia;C0751122:Severe myoclonic epilepsy in infancy;C1833661:Paroxysmal extreme pain disorder;C1855739:Channelopathy-associated congenital insensitivity to pain, autosomal recessive;C2751778:Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 228 of the SCN9A protein (p.Ile228Met). This variant is present in population databases (rs71428908, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with small fiber neuropathy and primary erythromelalgia (PMID: 22136189, 25993546, 29911575). ClinVar contains an entry for this variant (Variation ID: 198153). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SCN9A protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SCN9A function (PMID: 22136189, 23280954, 30316835). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Generalized epilepsy with febrile seizures plus, type 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 26, 2020

Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as 3B-VUS. Following criteria are met: 0103 - Both loss and gain of function are known mechanism of disease for this gene (OMIM). 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). 0112 - Variants in this gene are known to have reduced penetrance (PMID: 25993546). 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to methionine (exon 6). 0302 - Variant is present in gnomAD >=0.0002 and <0.001 for dominant indication. 0501 - Missense variant consistently predicted to be damaging by in silico tools or highly conserved with a major amino acid change. 0600 - Variant is located in an annotated domain or motif that does not have a well established function (ion transport domain 1; NCBI, PDB). 0705 - No comparable variants in relevant codon/region have previous evidence for pathogenicity. 0807 - The variant has been previously reported as a VUS in association with Small fibre neuropathy and Erythromelalgia (ClinVar, PMID: 22136189, PMID: 25993546, PMID: 30672368). 0905 - No published segregation evidence has been identified for this variant. 1002 - Moderate functional evidence supporting abnormal protein function. Studies showed that this variant results in a gain of function (PMID: 22136189, PMID: 23280954). 1205 - Variant is maternally inherited. -

Paroxysmal extreme pain disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 30, 2018

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

Pathogenic

0.72

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.39

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.75

.;D;D;.;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.22

LIST_S2

Uncertain

0.92

D;.;D;D;D

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.093

T;T;T;T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.2

M;M;M;.;.

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-2.8

D;.;.;.;.

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

D;.;.;.;.

Sift4G

Benign

0.10

T;T;.;.;.

Vest4

0.89

MVP

0.72

MPC

0.56

ClinPred

0.15

GERP RS

-3.4

Varity_R

0.87

gMVP

0.76

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