Genetic Variant SCN9A:p.Glu519Lys (chr2-166286383-C-T) – ACMG Classification: Uncertain_significance (0 pts)

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=0.08226916).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1 link	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	UniProt
SCN9A	ENST00000642356.2 link	c.1555G>A	p.Glu519Lys	missense_variant	Exon 11 of 27		NM_001365536.1	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11 link	c.1555G>A	p.Glu519Lys	missense_variant	Exon 11 of 27	5		ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5 link	c.1555G>A	p.Glu519Lys	missense_variant	Exon 11 of 27	5		ENSP00000386306.1	Q15858-3
SCN9A	ENST00000645907.1 link	c.1555G>A	p.Glu519Lys	missense_variant	Exon 11 of 27			ENSP00000495983.1	Q15858-4
SCN9A	ENST00000454569.6 link	c.1555G>A	p.Glu519Lys	missense_variant	Exon 11 of 15	1		ENSP00000413212.2	A0A0C4DG82

Frequencies

GnomAD3 genomes

AF:

0.000611

AC:

93

AN:

152160

Hom.:

0

Cov.:

32

show subpopulations

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

GnomAD3 exomes

AF:

0.000450

AC:

112

AN:

248934

Hom.:

1

AF XY:

0.000504

AC XY:

68

AN XY:

135038

show subpopulations

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 SAS exome

AF:

0.000131

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

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00124

Gnomad4 OTH exome

AF:

0.000646

GnomAD4 genome

AF:

0.000611

AC:

93

AN:

152276

Hom.:

0

Cov.:

32

AF XY:

0.000484

AC XY:

36

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00103

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000913

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:10Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:7

Oct 07, 2024

Athena Diagnostics

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

- -

Sep 09, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 10, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed as 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); 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) -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Oct 14, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;.

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

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

2-166286383-C-T

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