2-113062547-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1PP5BP4BS1_SupportingBS2

The NM_012275.3(IL36RN):c.338C>T(p.Ser113Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,614,064 control chromosomes in the GnomAD database, including 10 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 0.0026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 10 hom. )

Consequence

IL36RN
NM_012275.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11U:2O:1

Conservation

PhyloP100: 2.79

Variant links:

Genes affected

IL36RN (HGNC:15561): (interleukin 36 receptor antagonist) The protein encoded by this gene is a member of the interleukin 1 cytokine family. This cytokine was shown to specifically inhibit the activation of NF-kappaB induced by interleukin 1 family, member 6 (IL1F6). This gene and eight other interleukin 1 family genes form a cytokine gene cluster on chromosome 2. Two alternatively spliced transcript variants encoding the same protein have been reported. [provided by RefSeq, Jul 2008]

IL36RN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a disulfide_bond (size 146) in uniprot entity I36RA_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_012275.3

PP5

Variant 2-113062547-C-T is Pathogenic according to our data. Variant chr2-113062547-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 30490.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=5, Likely_pathogenic=3, not_provided=1}. Variant chr2-113062547-C-T is described in Lovd as [Pathogenic]. Variant chr2-113062547-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.017353624). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00258 (393/152278) while in subpopulation NFE AF= 0.00365 (248/68008). AF 95% confidence interval is 0.00327. There are 0 homozygotes in gnomad4. There are 192 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL36RN	NM_012275.3 link	c.338C>T	p.Ser113Leu	missense_variant	Exon 5 of 5	ENST00000393200.7	NP_036407.1	Q9UBH0A0A024R518
IL36RN	NM_173170.1 link	c.338C>T	p.Ser113Leu	missense_variant	Exon 5 of 5		NP_775262.1	Q9UBH0A0A024R518
IL36RN	XM_047443918.1 link	c.338C>T	p.Ser113Leu	missense_variant	Exon 6 of 6		XP_047299874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IL36RN	ENST00000393200.7 link	c.338C>T	p.Ser113Leu	missense_variant	Exon 5 of 5	1	NM_012275.3	ENSP00000376896.2	Q9UBH0
IL36RN	ENST00000346807.7 link	c.338C>T	p.Ser113Leu	missense_variant	Exon 5 of 5	1		ENSP00000259212.3	Q9UBH0
IL36RN	ENST00000437409.2 link	c.338C>T	p.Ser113Leu	missense_variant	Exon 4 of 4	1		ENSP00000409262.2	Q9UBH0C9JTH1
IL36RN	ENST00000514072.1 link	c.26C>T	p.Ser9Leu	missense_variant	Exon 1 of 2	3		ENSP00000475308.1	U3KPW9

Frequencies

GnomAD3 genomes

AF:

0.00258

AC:

393

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00621

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00365

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00288

AC:

724

AN:

251204

Hom.:

AF XY:

0.00302

AC XY:

410

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000810

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000457

Gnomad FIN exome

AF:

0.00705

Gnomad NFE exome

AF:

0.00448

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00344

AC:

5034

AN:

1461786

Hom.:

Cov.:

AF XY:

0.00338

AC XY:

2456

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.000805

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000487

Gnomad4 FIN exome

AF:

0.00649

Gnomad4 NFE exome

AF:

0.00393

Gnomad4 OTH exome

AF:

0.00364

GnomAD4 genome

AF:

0.00258

AC:

393

AN:

152278

Hom.:

Cov.:

AF XY:

0.00258

AC XY:

192

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000674

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00621

Gnomad4 NFE

AF:

0.00365

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00351

Hom.:

Bravo

AF:

0.00220

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00307

AC:

373

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00333

EpiControl

AF:

0.00391

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11Uncertain:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Mar 30, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 30, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3_very_strong, PS3_moderate, PS4_moderate -

Jun 11, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Common variant among individuals of European background (PMID: 24656634); Published functional studies suggest this variant results in reduced protein expression and partial impairment of capacity to repress an IL36RNmediated signaling cascade, however additional studies are needed to validate the functional effect of this variant in vivo (PMID: 27220475); 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: 25468355, 24131530, 23428889, 25458002, 25212972, 23792462, 21839423, 25989471, 22288582, 23648549, 22903787, 23303454, 23711932, 26589685, 25427108, 23909475, 23834760, 27038307, 27388993, 29030861, 30609409, 34426522, 38577038, 37414245, 26147717, 24656634, 27220475) -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IL36RN: PM3:Very Strong, PM2:Supporting, PS3:Supporting, BP4 -

Acrodermatitis continua suppurativa of Hallopeau

Pathogenic:3Uncertain:1

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The IL36RN p.Ser113Leu variant has been identified as a homozygous change or in trans with a second pathogenic IL36RN variant in multiple individuals with pustular psoriasis (PMID: 21839423, 23303454, 25427108 and others). It is also present in large population studies (815 heterozygous individuals, 1 homozygous individual, gnomAD v2.1.1). The relatively high frequency of this variant in the European population is thought to be due to a founder effect (PMID: 23303454). Functional studies have shown that the p.Ser113Leu variant is a hypomorphic allele that alters hydrophobic interactions within IL-36Ra as well as decreases protein levels (PMID: 27220475). Based on the ACMG/AMP guidelines, we classify the IL36RN p.Ser113Leu variant as a pathogenic change (PMID: 25741868). -

Nov 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 09, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 11, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Generalized pustular psoriasis

Pathogenic:2Uncertain:1Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Dec 07, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across a selection of the available literature, the IL36RN c.338C>T (p.Ser113Leu) missense variant has been identified in six patients in a homozygous state, in five patients in a compound heterozygous state, and in two patients in a heterozygous state. One heterozygous individual carried additional variants in the CARD14 gene (Onoufriadis et al. 2011; Setta-Kaffetzi et al. 2013; Abbas et al. 2013; Korber et al. 2013). The variant was also found in a heterozygous state in unaffected parents and was absent from 440 control individuals (Onoufriadis et al. 2011; Korber et al. 2013). This variant is reported at a frequency of 0.006635 in the European (non-Finnish) population of the Genome Aggregation Database. Two studies have evaluated the functional impact of this variant. Tauber et al. (2016) transfected the p.Ser113Leu variant form of the IL-36Ra protein into HEK293 cells and observed reduced protein expression. In addition, there was a decreased inhibitory effect on NF-kB activity compared to wild type activity. In a second study, Setta-Kaffetzi et al. (2013) used peripheral blood mononuclear cells from one patient who was homozygous for the p.Ser113Leu variant and one unrelated healthy individual and observed increased cytokine production in the presence of the variant compared to the control. Based on the collective evidence, the p.Ser113Leu variant is classified as pathogenic for generalized pustular psoriasis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 113 of the IL36RN protein (p.Ser113Leu). This variant is present in population databases (rs144478519, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with generalized pustular psoriasis (GPP), acrodermatitis continua of Hallopeau (ACH) (PMID: 21839423, 23303454, 23428889, 23648549, 25427108, 25458002, 26147717, 27388993, 28887889, 30036598). It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects IL36RN function (PMID: 27220475). 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. -

Mar 31, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser113Leu variant in IL36RN has been reported in >25 homozygous or compound heterozygous individuals with generalized pustular psoriasis and related psoriasis-associated pustular phenotypes. The p.Ser113Leu variant was identified with another disease-causing variant in IL36RN in > 5 individuals (Onoufriadis 2011 PMID: 21839423, Setta-Kaffetzi 2013 PMID: 23303454, Abbas 2013 PMID: 23428889, Korber 2013 PMID: 23648549, Navarini 2015 PMID: 25427108, Hussain 2015 PMID: 25458002, Rajan 2016 PMID: 26147717, Mossner 2018 PMID: 28887889). In one report, this variant was found at a statistically significantly higher proportion of cases to controls (Twelves 2019 PMID: 30036598). It also segregated with disease in one affected sibling from one family, who had a much less severe presentation (Rajan 2016 PMID: 26147717). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 30490) and has been identified in 0.6% (412/63940) of Finnish chromosomes and 0.4% (4619/1180018) of European chromosomes, including 10 total homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). In vitro functional studies provide some evidence that this variant reduces protein expression and slightly reduces the inhibitory function of IL36RN (Tauber 2016 PMID: 27220475); however, the residual function may signify that this is a hypomorphic allele. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as likely pathogenic for generalized pustular psoriasis, though its high frequency in control cohorts and in unaffected homozygotes suggest that this variant is hypomorphic and may only cause disease in some cases, with specific triggers, or only mild disease in some individuals. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1, PS3_Supporting. -

Autoinflammatory syndrome

Pathogenic:1

Apr 05, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

IL36RN-related disorder

Pathogenic:1

Aug 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The IL36RN c.338C>T variant is predicted to result in the amino acid substitution p.Ser113Leu. This variant has been reported in the homozygous and compound heterozygous states in individuals with generalized pustular psoriasis, palmarplantar pustulosis, and acrodermatitis continua of Hallopeau (Onoufriadis et al. 2011. PubMed ID: 21839423; Abbas et al. 2013. PubMed ID: 23428889; Setta-Kaffetzi et al. 2013. PubMed ID: 23303454). This variant was also identified in the heterozygous state in several individuals with generalized pustular psoriasis or palmarplantar pustulosis, suggesting that the p.Ser113Leu allele may have pathogenic potential even in the heterozygous state (Setta-Kaffetzi et al. 2013. PubMed ID: 23303454). Of note, this variant was also identified in the heterozygous state in one individual in a control cohort (Onoufriadis et al. 2011. PubMed ID: 21839423) and is reported in ~0.66% of alleles in individuals of European (Finnish) descent in gnomAD, which may be too frequent to cause disease in an autosomal dominant manner. Functional studies have shown that the p.Ser113Leu allele alters IL36RN protein expression and function (Tauber et al. 2016. PubMed ID: 27220475). Taken together, we interpret this variant as likely pathogenic for autosomal recessive disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Uncertain

0.090

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;T;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.87

.;D;T

M_CAP

Benign

0.085

MetaRNN

Benign

0.017

T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Pathogenic

3.3

M;M;.

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-5.4

D;D;D

REVEL

Uncertain

0.32

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

0.99

D;D;.

Vest4

0.89

MVP

0.51

MPC

0.41

ClinPred

0.10

GERP RS

4.2

Varity_R

0.71

gMVP

0.90

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