2-113062577-C-T

Position:

chr2-113062577-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_012275.3(IL36RN):c.368C>T(p.Thr123Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T123R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

IL36RN
NM_012275.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.417

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 8 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

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-113062577-C-G is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL36RN	NM_012275.3 linkuse as main transcript	c.368C>T	p.Thr123Met	missense_variant	5/5	ENST00000393200.7	NP_036407.1	Q9UBH0A0A024R518
IL36RN	NM_173170.1 linkuse as main transcript	c.368C>T	p.Thr123Met	missense_variant	5/5		NP_775262.1	Q9UBH0A0A024R518
IL36RN	XM_047443918.1 linkuse as main transcript	c.368C>T	p.Thr123Met	missense_variant	6/6		XP_047299874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
IL36RN	ENST00000393200.7 linkuse as main transcript	c.368C>T	p.Thr123Met	missense_variant	5/5	1	NM_012275.3	ENSP00000376896.2	Q9UBH0
IL36RN	ENST00000346807.7 linkuse as main transcript	c.368C>T	p.Thr123Met	missense_variant	5/5	1		ENSP00000259212.3	Q9UBH0
IL36RN	ENST00000437409.2 linkuse as main transcript	c.368C>T	p.Thr123Met	missense_variant	4/4	1		ENSP00000409262.2	Q9UBH0C9JTH1
IL36RN	ENST00000514072.1 linkuse as main transcript	c.56C>T	p.Thr19Met	missense_variant	1/2	3		ENSP00000475308.1	U3KPW9

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251120

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135786

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.0000467

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461618

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Generalized pustular psoriasis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 27, 2022

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 123 of the IL36RN protein (p.Thr123Met). This variant is present in population databases (rs397514629, gnomAD 0.01%). 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. Experimental studies have shown that this missense change affects IL36RN function (PMID: 26147717, 27220475). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 662407). This missense change has been observed in individual(s) with generalized pustular psoriasis (PMID: 23834760, 25212972, 25615897, 26147717). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;T

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Benign

0.32

LIST_S2

Uncertain

0.86

.;D

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

3.5

M;M

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.011

D;D

Polyphen

1.0

D;D

Vest4

0.31

MutPred

0.85

Gain of catalytic residue at T123 (P = 0.0351);Gain of catalytic residue at T123 (P = 0.0351);

MVP

0.84

MPC

0.28

ClinPred

0.79

GERP RS

4.2

Varity_R

0.32

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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