2-113062148-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_012275.3(IL36RN):c.140A>G(p.Asn47Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,613,984 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N47I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0023 ( 12 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 33 hom. )

Consequence

IL36RN
NM_012275.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.32

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

psoriasis 14, pustular
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
pustulosis palmaris et plantaris
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

IL36RN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048855245).

BP6

Variant 2-113062148-A-G is Benign according to our data. Variant chr2-113062148-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 529887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00228 (347/152164) while in subpopulation EAS AF = 0.049 (253/5166). AF 95% confidence interval is 0.044. There are 12 homozygotes in GnomAd4. There are 208 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
IL36RN	NM_012275.3 link	c.140A>G	p.Asn47Ser	missense_variant	Exon 4 of 5	ENST00000393200.7	NP_036407.1
IL36RN	NM_173170.1 link	c.140A>G	p.Asn47Ser	missense_variant	Exon 4 of 5		NP_775262.1
IL36RN	XM_047443918.1 link	c.140A>G	p.Asn47Ser	missense_variant	Exon 5 of 6		XP_047299874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
IL36RN	ENST00000393200.7 link	c.140A>G	p.Asn47Ser	missense_variant	Exon 4 of 5	1	NM_012275.3	ENSP00000376896.2
IL36RN	ENST00000346807.7 link	c.140A>G	p.Asn47Ser	missense_variant	Exon 4 of 5	1		ENSP00000259212.3
IL36RN	ENST00000437409.2 link	c.140A>G	p.Asn47Ser	missense_variant	Exon 3 of 4	1		ENSP00000409262.2

Frequencies

GnomAD3 genomes

AF:

0.00230

AC:

350

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0493

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00479

AC:

1204

AN:

251190

AF XY:

0.00444

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0561

Gnomad FIN exome

AF:

0.00171

Gnomad NFE exome

AF:

0.000484

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00148

AC:

2170

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

1066

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.000597

AC:

AN:

33480

American (AMR)

AF:

0.000201

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0369

AC:

1465

AN:

39700

South Asian (SAS)

AF:

0.00148

AC:

128

AN:

86258

European-Finnish (FIN)

AF:

0.00170

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000258

AC:

287

AN:

1111956

Other (OTH)

AF:

0.00280

AC:

169

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

140

281

421

562

702

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00228

AC:

347

AN:

152164

Hom.:

Cov.:

AF XY:

0.00280

AC XY:

208

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.000963

AC:

AN:

41516

American (AMR)

AF:

0.000392

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.0490

AC:

253

AN:

5166

South Asian (SAS)

AF:

0.00311

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

67970

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00163

Hom.:

Bravo

AF:

0.00241

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00460

AC:

558

Asia WGS

AF:

0.0260

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Aug 23, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26589685, 33560533, 32613680, 31180159, 27542682)

Generalized pustular psoriasis

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

Acrodermatitis continua suppurativa of Hallopeau

Benign:1

Oct 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autoinflammatory syndrome

Benign:1

Dec 23, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

T;T;.

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.0

.;T;T

MetaRNN

Benign

0.0049

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.1

M;M;.

PhyloP100

1.3

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.4

N;N;N

REVEL

Benign

0.28

Sift

Uncertain

0.027

D;D;D

Sift4G

Uncertain

0.018

D;D;T

Vest4

0.21

ClinPred

0.043

GERP RS

4.2

PromoterAI

-0.034

Neutral

(source)

Varity_R

0.10

gMVP

0.40

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over