rs148755083

Variant names:

• chr2-113060943-T-C
• rs148755083
• NM_012275.3:c.115+6T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 8P and 6B. PP5_Very_Strong BP4 BS1_Supporting BS2

The NM_012275.3(IL36RN):​c.115+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,608,740 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (3 hom.)
• Consequence: IL36RN NM_012275.3 splice_region, intron
• Scores: Splicing: ADA: 0.6933
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 2.02
• Publications: 57 publications found

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 Gene-Disease associations (from GenCC):

• psoriasis 14, pustular

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• pustulosis palmaris et plantaris

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP5: Variant 2-113060943-T-C is Pathogenic according to our data. Variant chr2-113060943-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 40005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000342 (52/152256) while in subpopulation EAS AF = 0.01 (52/5178). AF 95% confidence interval is 0.00787. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL36RN	NM_012275.3	c.115+6T>C		splice_region_variant, intron_variant	Intron 3 of 4	ENST00000393200.7	NP_036407.1
IL36RN	NM_173170.1	c.115+6T>C		splice_region_variant, intron_variant	Intron 3 of 4		NP_775262.1
IL36RN	XM_047443918.1	c.115+6T>C		splice_region_variant, intron_variant	Intron 4 of 5		XP_047299874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL36RN	ENST00000393200.7	c.115+6T>C		splice_region_variant, intron_variant	Intron 3 of 4	1	NM_012275.3	ENSP00000376896.2
IL36RN	ENST00000346807.7	c.115+6T>C		splice_region_variant, intron_variant	Intron 3 of 4	1		ENSP00000259212.3
IL36RN	ENST00000437409.2	c.115+6T>C		splice_region_variant, intron_variant	Intron 2 of 3	1		ENSP00000409262.2

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00100 AC: 252 AN: 251330 AF XY: 0.000942

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0135

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000225 AC: 327 AN: 1456484 Hom.: 3 Cov.: 29 AF XY: 0.000219 AC XY: 159 AN XY: 725028

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00749 AC: 297 AN: 39668

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107054

Other (OTH) AF: 0.000448 AC: 27 AN: 60234

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152256 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74454

African (AFR) AF: 0.00 AC: 0 AN: 41538

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0100 AC: 52 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000348 Hom.: 0

Bravo AF: 0.000646

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acrodermatitis continua suppurativa of Hallopeau Pathogenic:5

Dec 29, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 24, 2023

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1+PM3_VeryStrong+PP4+PP1_Strong+BS1 -

-

Medical Laboratory Center, Huzhou Maternal and Child Health Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Generalized pustular psoriasis Pathogenic:3

Feb 28, 2020

Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 3 of the IL36RN gene. It does not directly change the encoded amino acid sequence of the IL36RN protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs148755083, gnomAD 1.3%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with generalized pustular psoriasis (PMID: 22903787, 23303454, 23698098, 23863864, 24979538, 26589685, 28063630). It is commonly reported in individuals of Japanese and Chinese ancestry (PMID: 22903787, 23303454, 23698098, 23863864, 24979538, 26589685, 28063630). ClinVar contains an entry for this variant (Variation ID: 40005). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 22903787, 23698098). For these reasons, this variant has been classified as Pathogenic. -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

NG_031864.1(NM_012275.2):c.115+6T>C in the IL36RN gene has an allele frequency of 0.013 in East Asian subpopulation in the gnomAD database. Farooq M et al. reported one patient with generalized pustular psoriasis was compound heterozygous for mutations c.115+6T>C and c.368C>G (p.Thr123Arg) and another was compound heterozygous for mutations c.28C>T (p.Arg10*) and c.115+6T>C in the IL36RN gene (PMID: 22903787). Shu D et al. reported two siblings with deficiency of IL-36Ra, from a Chinese Daur family, who both carried the homozygous IL36RN c.115+6T>C mutation, while other four healthy family members carried heterozygous c.115+6T>C mutations (PMID: 24979538). Experimental studies have shown that this intronic change causes skipping of exon 3, resulting in a truncated protein product (PMID: 23698098; 22903787). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS3, PM3_Strong, PP1, PP4. -

not provided Pathogenic:1

Nov 08, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Most common variant observed in Chinese patients and suggested to be a founder variant in Asian populations (PMID: 23863864, 26589685); Non-canonical splice site variant demonstrated to result in loss-of-function (PMID: 22903787); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 24979538, 24717243, 34339530, 32613680, 31062396, 26104679, 31589614, 27900482, 23698098, 31353537, 30835863, 26627198, 34539730, 22903787, 23303454, 25615897, 28369922, 29454537, 29665114, 29619998, 25468355, 25212972, 33415665, 34806229, 35922198, 36331855, 36704338, 36843341, 35426442, 35575468, 29655177, 23863864, 26589685) -

Autoinflammatory syndrome Pathogenic:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

IL36RN-related disorder Pathogenic:1

Feb 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The IL36RN c.115+6T>C variant is predicted to interfere with splicing. RNA studies have shown this variant leads to skipping of exon 3 (Farooq et al. 2013. PubMed ID: 22903787). This variant, in the compound heterozygous and homozygous states, has been reported to be associated with generalized pustular psoriasis with incomplete penetrance (Sugiura et al. 2012. PubMed: 23303454; Shiratori et al. 2015. PubMed ID: 25615897; Liang et al. 2017. PubMed ID: 27900482; Setta-Kaffetzi et al. 2013. PubMed ID: 23303454). This variant is reported in 1.3% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.94
PhyloP100		2.0
Mutation Taster		=41/59	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.69
dbscSNV1_RF	Benign	0.63
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.48		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs148755083; hg19: chr2-113818520;