rs187015338

chr2-113060926-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012275.3(IL36RN):c.104A>G(p.Lys35Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,613,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: IL36RN NM_012275.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 1.87

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.077201664).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL36RN	NM_012275.3	c.104A>G	p.Lys35Arg	missense_variant	3/5	ENST00000393200.7
IL36RN	NM_173170.1	c.104A>G	p.Lys35Arg	missense_variant	3/5
IL36RN	XM_047443918.1	c.104A>G	p.Lys35Arg	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL36RN	ENST00000393200.7	c.104A>G	p.Lys35Arg	missense_variant	3/5	1	NM_012275.3	P1
IL36RN	ENST00000346807.7	c.104A>G	p.Lys35Arg	missense_variant	3/5	1		P1
IL36RN	ENST00000437409.2	c.104A>G	p.Lys35Arg	missense_variant	2/4	1		P1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152178 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000183 AC: 46 AN: 251424 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000111 AC: 162 AN: 1461306 Hom.: 0 Cov.: 31 AF XY: 0.000105 AC XY: 76 AN XY: 727010

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000580

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74474

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000686 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Acrodermatitis continua suppurativa of Hallopeau Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2013

- -

Generalized pustular psoriasis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 11, 2023

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 35 of the IL36RN protein (p.Lys35Arg). This variant is present in population databases (rs187015338, gnomAD 0.05%). This missense change has been observed in individual(s) with generalized pustular psoriasis (PMID: 23303454). ClinVar contains an entry for this variant (Variation ID: 160373). 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 tolerated. Experimental studies have shown that this missense change does not substantially affect 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.082	T;T;.
Eigen	Benign	-0.065
Eigen_PC	Benign	0.080
FATHMM_MKL	Benign	0.68	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.077	T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.0	L;L;.
MutationTaster	Benign	0.91	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.65	N;N;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.013	D;D;D
Sift4G	Benign	0.14	T;T;T
Polyphen		0.27	B;B;.
Vest4		0.73
MVP		0.64
MPC		0.083
ClinPred		0.070	T
GERP RS		4.7
Varity_R		0.071
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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

Other links and lift over

dbSNP: rs187015338; hg19: chr2-113818503;