rs148755083

chr2-113060943-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5 BP4 BS2

The NM_012275.3(IL36RN):c.115+6T>C variant causes a splice donor 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (3 hom.)
• Consequence: IL36RN NM_012275.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.6933
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• Conservation: PhyloP100: 2.02

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 -4 ACMG points.

• PP5: Variant 2-113060943-T-C is Pathogenic according to our data. Variant chr2-113060943-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 40005.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Likely_pathogenic=3, Uncertain_significance=1}. Variant chr2-113060943-T-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).. Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL36RN	NM_012275.3	c.115+6T>C		splice_donor_region_variant, intron_variant		ENST00000393200.7
IL36RN	NM_173170.1	c.115+6T>C		splice_donor_region_variant, intron_variant
IL36RN	XM_047443918.1	c.115+6T>C		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL36RN	ENST00000393200.7	c.115+6T>C		splice_donor_region_variant, intron_variant		1	NM_012275.3	P1
IL36RN	ENST00000346807.7	c.115+6T>C		splice_donor_region_variant, intron_variant		1		P1
IL36RN	ENST00000437409.2	c.115+6T>C		splice_donor_region_variant, intron_variant		1		P1

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

GnomAD3 exomes AF: 0.00100 AC: 252 AN: 251330 Hom.: 2 AF XY: 0.000942 AC XY: 128 AN XY: 135832

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 SAS exome AF: 0.0000654

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00749

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000448

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0100

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000110 Hom.: 0

Bravo AF: 0.000646

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Generalized pustular psoriasis Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	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 disrupted 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 introduces a premature termination codon (PMID: 22903787, 23698098). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	Feb 28, 2020	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -

Acrodermatitis continua suppurativa of Hallopeau Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Mar 24, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 29, 2022	- -

IL36RN-related condition Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 2024

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. -

Autoinflammatory syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
Cadd	Benign	19
Dann	Benign	0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs148755083; hg19: chr2-113818520;