2-113062235-C-T

Position:

chr2-113062235-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP5BP4BS2

The NM_012275.3(IL36RN):c.227C>T(p.Pro76Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,613,982 control chromosomes in the GnomAD database, including 2 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 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 2 hom. )

Consequence

IL36RN
NM_012275.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.64

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 -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 2-113062235-C-T is Pathogenic according to our data. Variant chr2-113062235-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 575254.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=1, Uncertain_significance=2}.

BP4

Computational evidence support a benign effect (MetaRNN=0.19842246). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
IL36RN	NM_012275.3 linkuse as main transcript	c.227C>T	p.Pro76Leu	missense_variant	4/5	ENST00000393200.7	NP_036407.1
IL36RN	NM_173170.1 linkuse as main transcript	c.227C>T	p.Pro76Leu	missense_variant	4/5		NP_775262.1
IL36RN	XM_047443918.1 linkuse as main transcript	c.227C>T	p.Pro76Leu	missense_variant	5/6		XP_047299874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
IL36RN	ENST00000393200.7 linkuse as main transcript	c.227C>T	p.Pro76Leu	missense_variant	4/5	1	NM_012275.3	ENSP00000376896	P1
IL36RN	ENST00000346807.7 linkuse as main transcript	c.227C>T	p.Pro76Leu	missense_variant	4/5	1		ENSP00000259212	P1
IL36RN	ENST00000437409.2 linkuse as main transcript	c.227C>T	p.Pro76Leu	missense_variant	3/4	1		ENSP00000409262	P1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152046

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:

0.000964

Gnomad SAS

AF:

0.000831

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000287

AC:

AN:

251288

Hom.:

AF XY:

0.000309

AC XY:

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000924

Gnomad SAS exome

AF:

0.000719

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000255

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000241

AC:

352

AN:

1461818

Hom.:

Cov.:

AF XY:

0.000254

AC XY:

185

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000605

Gnomad4 SAS exome

AF:

0.000649

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000221

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.000171

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.000832

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000466

Hom.:

Bravo

AF:

0.000200

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000329

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Generalized pustular psoriasis

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 09, 2019	The IL36RN gene is one of at least three genes in which variants cause Generalized Pustular Psoriasis. The IL36RN c.227C>T (p.Pro76Leu) variant has been reported five studies and is found in a total of 12 probands including two in a homozygous state, two in a compound heterozygous state, and nine in a heterozygous state (Korber et al. 2013; Li et al. 2013; Mossner et al. 2015; Wang et al. 2015; Arakawa et al. 2016). One of the homozygotes with Turkish ancestry was from consanguineous parents (Korber et al. 2013). Three of the heterozygotes also carried a homozygous pathogenic variant (Wang et al. 2015). The p.Pro76Leu variant was found in two of 1495 healthy controls and is reported at a frequency of 0.005376 in the Chinese Dai in Xishuangbanna population of the 1000 Genomes Project Database. In vitro analysis in HEK293T cells did not detect any IL-36Ra protein and found no reduction in NF-kB activity which is repressed in wildtype in association with the p.Pro76Leu variant (Tauber et al. 2016). This variant affects a highly conserved residue of the protein and causes an absence of protein product and function. Based on the available evidence, this variant is classified as likely 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 proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 76 of the IL36RN protein (p.Pro76Leu). This variant is present in population databases (rs139497891, gnomAD 0.09%). This missense change has been observed in individual(s) with generalized pustular psoriasis (PMID: 23648549, 23863864, 26589685, 27096382, 33729564, 34339530). ClinVar contains an entry for this variant (Variation ID: 575254). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 10, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Uncertain

0.057

BayesDel_noAF

Pathogenic

0.24

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

T;T;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.70

.;T;T

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Uncertain

0.53

MutationAssessor

Pathogenic

3.3

M;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-6.4

D;D;D

REVEL

Uncertain

0.58

Sift

Benign

0.16

T;T;T

Sift4G

Benign

0.076

T;T;D

Polyphen

1.0

D;D;.

Vest4

0.71

MVP

0.80

MPC

0.53

ClinPred

0.35

GERP RS

5.2

Varity_R

0.32

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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