2-113060943-T-C

Position:

chr2-113060943-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4

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:10

Conservation

PhyloP100: 2.02

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_pathogenic. Variant got 7 ACMG points.

PP5

Variant 2-113060943-T-C is Pathogenic according to our data. Variant chr2-113060943-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
IL36RN	NM_012275.3 linkuse as main transcript	c.115+6T>C	splice_region_variant, intron_variant	ENST00000393200.7	NP_036407.1	Q9UBH0A0A024R518
IL36RN	NM_173170.1 linkuse as main transcript	c.115+6T>C	splice_region_variant, intron_variant		NP_775262.1	Q9UBH0A0A024R518
IL36RN	XM_047443918.1 linkuse as main transcript	c.115+6T>C	splice_region_variant, intron_variant		XP_047299874.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
IL36RN	ENST00000393200.7 linkuse as main transcript	c.115+6T>C	splice_region_variant, intron_variant	1	NM_012275.3	ENSP00000376896.2	Q9UBH0
IL36RN	ENST00000346807.7 linkuse as main transcript	c.115+6T>C	splice_region_variant, intron_variant	1		ENSP00000259212.3	Q9UBH0
IL36RN	ENST00000437409.2 linkuse as main transcript	c.115+6T>C	splice_region_variant, intron_variant	1		ENSP00000409262.2	Q9UBH0C9JTH1

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000942

AC XY:

128

AN XY:

135832

show subpopulations

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.:

Cov.:

AF XY:

0.000219

AC XY:

159

AN XY:

725028

show subpopulations

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:

AN:

152256

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74454

show subpopulations

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.:

Bravo

AF:

0.000646

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Acrodermatitis continua suppurativa of Hallopeau

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PS3+PM3_VeryStrong+PP4+PP1_Moderate+BS1 -
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	- -
Pathogenic, no assertion criteria provided	research	Medical Laboratory Center, Huzhou Maternal and Child Health Hospital	-	- -

Generalized pustular psoriasis

Pathogenic:3

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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -

Autoinflammatory syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

IL36RN-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

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

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