2-113060902-T-C

Position:

chr2-113060902-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_012275.3(IL36RN):c.80T>C(p.Leu27Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,614,008 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000045 ( 1 hom. )

Consequence

IL36RN
NM_012275.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.47

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 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-113060902-T-C is Pathogenic according to our data. Variant chr2-113060902-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 30489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-113060902-T-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.07388443). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
IL36RN	NM_012275.3 linkuse as main transcript	c.80T>C	p.Leu27Pro	missense_variant	3/5	ENST00000393200.7
IL36RN	NM_173170.1 linkuse as main transcript	c.80T>C	p.Leu27Pro	missense_variant	3/5
IL36RN	XM_047443918.1 linkuse as main transcript	c.80T>C	p.Leu27Pro	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
IL36RN	ENST00000393200.7 linkuse as main transcript	c.80T>C	p.Leu27Pro	missense_variant	3/5	1	NM_012275.3	P1
IL36RN	ENST00000346807.7 linkuse as main transcript	c.80T>C	p.Leu27Pro	missense_variant	3/5	1		P1
IL36RN	ENST00000437409.2 linkuse as main transcript	c.80T>C	p.Leu27Pro	missense_variant	2/4	1		P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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:

0.000223

AC:

AN:

251444

Hom.:

AF XY:

0.000191

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.0000452

AC:

AN:

1461788

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00125

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000337

Hom.:

Bravo

AF:

0.000125

ExAC

AF:

0.000272

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Acrodermatitis continua suppurativa of Hallopeau

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 18, 2011

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2017

- -

Generalized pustular psoriasis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 19, 2023

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 27 of the IL36RN protein (p.Leu27Pro). This variant is present in population databases (rs387906914, gnomAD 0.1%). This missense change has been observed in individual(s) with deficiency of interleukin-36 receptor antagonist (DITRA) and generalized pustular psoriasis (PMID: 21848462, 24019411, 29892664). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30489). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects IL36RN function (PMID: 21848462, 27220475). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Uncertain

0.028

BayesDel_noAF

Pathogenic

0.22

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;D;.

Eigen

Benign

0.093

Eigen_PC

Benign

-0.041

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.59

.;T;T

M_CAP

Benign

0.067

MetaRNN

Benign

0.074

T;T;T

MetaSVM

Uncertain

-0.28

MutationAssessor

Benign

1.6

L;L;.

MutationTaster

Benign

0.90

N;N

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

0.99

D;D;.

Vest4

0.94

MutPred

0.55

Gain of disorder (P = 0.0212);Gain of disorder (P = 0.0212);Gain of disorder (P = 0.0212);

MVP

0.77

MPC

0.43

ClinPred

0.18

GERP RS

2.4

Varity_R

0.72

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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