2-113062547-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP5BP4BS1_SupportingBS2

The NM_012275.3(IL36RN):c.338C>T(p.Ser113Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,614,064 control chromosomes in the GnomAD database, including 10 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 0.0026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 10 hom. )

Consequence

IL36RN
NM_012275.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12U:2O:1

Conservation

PhyloP100: 2.79

Publications

45 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Genomics England PanelApp
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: Likely_benign. The variant received -5 ACMG points.

PP5

Variant 2-113062547-C-T is Pathogenic according to our data. Variant chr2-113062547-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 30490.

BP4

Computational evidence support a benign effect (MetaRNN=0.017353624). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00258 (393/152278) while in subpopulation NFE AF = 0.00365 (248/68008). AF 95% confidence interval is 0.00327. There are 0 homozygotes in GnomAd4. There are 192 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 10 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012275.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL36RN	NM_012275.3	MANE Select	c.338C>T	p.Ser113Leu	missense	Exon 5 of 5	NP_036407.1	Q9UBH0
	IL36RN	NM_173170.1		c.338C>T	p.Ser113Leu	missense	Exon 5 of 5	NP_775262.1	Q9UBH0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL36RN	ENST00000393200.7	TSL:1 MANE Select	c.338C>T	p.Ser113Leu	missense	Exon 5 of 5	ENSP00000376896.2	Q9UBH0
IL36RN	ENST00000346807.7	TSL:1	c.338C>T	p.Ser113Leu	missense	Exon 5 of 5	ENSP00000259212.3	Q9UBH0
IL36RN	ENST00000437409.2	TSL:1	c.338C>T	p.Ser113Leu	missense	Exon 4 of 4	ENSP00000409262.2	Q9UBH0

Frequencies

GnomAD3 genomes

AF:

0.00258

AC:

393

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00621

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00365

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00288

AC:

724

AN:

251204

AF XY:

0.00302

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000810

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00705

Gnomad NFE exome

AF:

0.00448

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00344

AC:

5034

AN:

1461786

Hom.:

Cov.:

AF XY:

0.00338

AC XY:

2456

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33480

American (AMR)

AF:

0.000805

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000487

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00649

AC:

346

AN:

53320

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00393

AC:

4371

AN:

1112010

Other (OTH)

AF:

0.00364

AC:

220

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

333

666

1000

1333

1666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

304

456

608

760

<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:

0.00258

AC:

393

AN:

152278

Hom.:

Cov.:

AF XY:

0.00258

AC XY:

192

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.000674

AC:

AN:

41558

American (AMR)

AF:

0.00288

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000622

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00621

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00365

AC:

248

AN:

68008

Other (OTH)

AF:

0.00190

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00363

Hom.:

Bravo

AF:

0.00220

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00307

AC:

373

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00333

EpiControl

AF:

0.00391

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Acrodermatitis continua suppurativa of Hallopeau (5)

not provided (4)

Generalized pustular psoriasis (4)

Autoinflammatory syndrome (1)

IL36RN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Uncertain

0.090

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.085

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.67

MutationAssessor

Pathogenic

3.3

PhyloP100

2.8

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-5.4

REVEL

Uncertain

0.32

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

0.99

Vest4

0.89

MVP

0.51

MPC

0.41

ClinPred

0.10

GERP RS

4.2

PromoterAI

0.0016

Neutral

(source)

Varity_R

0.71

gMVP

0.90

Mutation Taster

=34/66

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over