2-113062899-T-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_012275.3(IL36RN):​c.*222T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 588,930 control chromosomes in the GnomAD database, including 125,218 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 0.65 ( 32678 hom., cov: 32)
Exomes 𝑓: 0.65 ( 92540 hom. )

Consequence

IL36RN
NM_012275.3 3_prime_UTR

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -2.79

Publications

13 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.98).
BP6
Variant 2-113062899-T-C is Benign according to our data. Variant chr2-113062899-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 330783.
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IL36RNNM_012275.3 linkc.*222T>C 3_prime_UTR_variant Exon 5 of 5 ENST00000393200.7 NP_036407.1 Q9UBH0A0A024R518
IL36RNNM_173170.1 linkc.*222T>C 3_prime_UTR_variant Exon 5 of 5 NP_775262.1 Q9UBH0A0A024R518
IL36RNXM_047443918.1 linkc.*222T>C 3_prime_UTR_variant Exon 6 of 6 XP_047299874.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IL36RNENST00000393200.7 linkc.*222T>C 3_prime_UTR_variant Exon 5 of 5 1 NM_012275.3 ENSP00000376896.2 Q9UBH0
IL36RNENST00000346807.7 linkc.*222T>C 3_prime_UTR_variant Exon 5 of 5 1 ENSP00000259212.3 Q9UBH0
IL36RNENST00000514072.1 linkc.*49+173T>C intron_variant Intron 1 of 1 3 ENSP00000475308.1 U3KPW9
IL36RNENST00000437409.2 linkc.*222T>C downstream_gene_variant 1 ENSP00000409262.2 Q9UBH0C9JTH1

Frequencies

GnomAD3 genomes
AF:
0.652
AC:
99091
AN:
151924
Hom.:
32625
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.707
Gnomad AMI
AF:
0.757
Gnomad AMR
AF:
0.663
Gnomad ASJ
AF:
0.688
Gnomad EAS
AF:
0.708
Gnomad SAS
AF:
0.801
Gnomad FIN
AF:
0.629
Gnomad MID
AF:
0.741
Gnomad NFE
AF:
0.601
Gnomad OTH
AF:
0.685
GnomAD4 exome
AF:
0.646
AC:
282209
AN:
436888
Hom.:
92540
Cov.:
3
AF XY:
0.655
AC XY:
151507
AN XY:
231354
show subpopulations
African (AFR)
AF:
0.712
AC:
8881
AN:
12472
American (AMR)
AF:
0.698
AC:
14659
AN:
20998
Ashkenazi Jewish (ASJ)
AF:
0.674
AC:
9136
AN:
13552
East Asian (EAS)
AF:
0.729
AC:
21230
AN:
29114
South Asian (SAS)
AF:
0.797
AC:
37491
AN:
47058
European-Finnish (FIN)
AF:
0.606
AC:
16239
AN:
26776
Middle Eastern (MID)
AF:
0.741
AC:
1414
AN:
1908
European-Non Finnish (NFE)
AF:
0.603
AC:
156877
AN:
259982
Other (OTH)
AF:
0.651
AC:
16282
AN:
25028
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.495
Heterozygous variant carriers
0
5107
10214
15322
20429
25536
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
808
1616
2424
3232
4040
<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:
0.652
AC:
99200
AN:
152042
Hom.:
32678
Cov.:
32
AF XY:
0.656
AC XY:
48748
AN XY:
74350
show subpopulations
African (AFR)
AF:
0.707
AC:
29308
AN:
41442
American (AMR)
AF:
0.664
AC:
10145
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
0.688
AC:
2386
AN:
3470
East Asian (EAS)
AF:
0.707
AC:
3655
AN:
5170
South Asian (SAS)
AF:
0.802
AC:
3863
AN:
4818
European-Finnish (FIN)
AF:
0.629
AC:
6654
AN:
10576
Middle Eastern (MID)
AF:
0.738
AC:
217
AN:
294
European-Non Finnish (NFE)
AF:
0.601
AC:
40829
AN:
67960
Other (OTH)
AF:
0.689
AC:
1453
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
1769
3538
5308
7077
8846
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
804
1608
2412
3216
4020
<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:
0.625
Hom.:
37045
Bravo
AF:
0.658
Asia WGS
AF:
0.790
AC:
2743
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Acrodermatitis continua suppurativa of Hallopeau Uncertain:1
-
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Patients with Generalized pustular Psoriasis, with certain mutations, respond very well to IL-1 antagonists like Anakinra, as IL36RN mutations upregulate IL-1. IL36RN gene encodes IL-36 receptor antagonist (IL-36Ra), which is required for subsequent activation of intracellular NF-κB and mitogen-activated protein kinase pathways. However, the role of rs2515401 is yet to be ascertained. -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Generalized pustular psoriasis Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.98
CADD
Benign
0.34
DANN
Benign
0.42
PhyloP100
-2.8
PromoterAI
-0.026
Neutral
Mutation Taster
=100/0
polymorphism (auto)

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

Other links and lift over

dbSNP: rs2515401; hg19: chr2-113820476; API