2-113062547-C-T

Position:

• chr2-113062547-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1 PP5 BP4 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:3 O:1
• Conservation: PhyloP100: 2.79

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 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: {Likely_pathogenic=2, not_provided=1, Uncertain_significance=3, Pathogenic=5}. 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.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL36RN	NM_012275.3	c.338C>T	p.Ser113Leu	missense_variant	5/5	ENST00000393200.7	NP_036407.1
IL36RN	NM_173170.1	c.338C>T	p.Ser113Leu	missense_variant	5/5		NP_775262.1
IL36RN	XM_047443918.1	c.338C>T	p.Ser113Leu	missense_variant	6/6		XP_047299874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL36RN	ENST00000393200.7	c.338C>T	p.Ser113Leu	missense_variant	5/5	1	NM_012275.3	ENSP00000376896	P1
IL36RN	ENST00000346807.7	c.338C>T	p.Ser113Leu	missense_variant	5/5	1		ENSP00000259212	P1
IL36RN	ENST00000437409.2	c.338C>T	p.Ser113Leu	missense_variant	4/4	1		ENSP00000409262	P1
IL36RN	ENST00000514072.1	c.29C>T	p.Ser10Leu	missense_variant	1/2	3		ENSP00000475308

Frequencies

GnomAD3 genomes AF: 0.00258 AC: 393 AN: 152160 Hom.: 0 Cov.: 32

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.: 1 AF XY: 0.00302 AC XY: 410 AN XY: 135814

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.: 10 Cov.: 32 AF XY: 0.00338 AC XY: 2456 AN XY: 727206

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.: 0 Cov.: 32 AF XY: 0.00258 AC XY: 192 AN XY: 74458

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.: 3

Bravo AF: 0.00220

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00307 AC: 373

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.00333

EpiControl AF: 0.00391

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10 Uncertain:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 01, 2023	PM3_very_strong, PS3_moderate, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2024	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) -

Acrodermatitis continua suppurativa of Hallopeau Pathogenic:3 Uncertain:1

Likely pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	-	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). -

Generalized pustular psoriasis Pathogenic:2 Uncertain:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 07, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2022	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 31, 2024	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

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 05, 2022

- -

IL36RN-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 27, 2024

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	T
BayesDel_noAF	Uncertain	0.090
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.87	.;D;T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.017	T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Pathogenic	3.3	M;M;.
MutationTaster	Benign	0.62	D;D
PrimateAI	Benign	0.47	T
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	T
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

Other links and lift over

dbSNP: rs144478519; hg19: chr2-113820124; COSMIC: COSV99059878;