2-113059446-T-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_012275.3(IL36RN):​c.8T>C​(p.Leu3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

IL36RN
NM_012275.3 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.00

Publications

1 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: Likely_benign. The variant received -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.2427046).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IL36RNNM_012275.3 linkc.8T>C p.Leu3Pro missense_variant Exon 2 of 5 ENST00000393200.7 NP_036407.1 Q9UBH0A0A024R518
IL36RNNM_173170.1 linkc.8T>C p.Leu3Pro missense_variant Exon 2 of 5 NP_775262.1 Q9UBH0A0A024R518
IL36RNXM_047443918.1 linkc.8T>C p.Leu3Pro missense_variant Exon 3 of 6 XP_047299874.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IL36RNENST00000393200.7 linkc.8T>C p.Leu3Pro missense_variant Exon 2 of 5 1 NM_012275.3 ENSP00000376896.2 Q9UBH0
IL36RNENST00000346807.7 linkc.8T>C p.Leu3Pro missense_variant Exon 2 of 5 1 ENSP00000259212.3 Q9UBH0
IL36RNENST00000437409.2 linkc.8T>C p.Leu3Pro missense_variant Exon 1 of 4 1 ENSP00000409262.2 Q9UBH0C9JTH1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.0000239
AC:
6
AN:
251466
AF XY:
0.0000147
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000173
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461684
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727132
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33478
American (AMR)
AF:
0.000157
AC:
7
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86244
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5604
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1112008
Other (OTH)
AF:
0.00
AC:
0
AN:
60372
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.454
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Generalized pustular psoriasis Uncertain:1
Jun 13, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 3 of the IL36RN protein (p.Leu3Pro). This variant is present in population databases (rs766403906, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with IL36RN-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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
Uncertain
0.45
BayesDel_addAF
Benign
-0.031
T
BayesDel_noAF
Uncertain
-0.030
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.16
T;T;.
Eigen
Benign
0.18
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Benign
0.62
D
LIST_S2
Benign
0.57
.;T;T
M_CAP
Uncertain
0.096
D
MetaRNN
Benign
0.24
T;T;T
MetaSVM
Uncertain
-0.27
T
MutationAssessor
Benign
1.6
L;L;.
PhyloP100
2.0
PrimateAI
Pathogenic
0.80
T
PROVEAN
Benign
0.27
N;N;N
REVEL
Uncertain
0.49
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.0030
D;D;D
Polyphen
0.46
P;P;.
Vest4
0.39
MutPred
0.45
Gain of disorder (P = 0.0084);Gain of disorder (P = 0.0084);Gain of disorder (P = 0.0084);
MVP
0.81
MPC
0.66
ClinPred
0.24
T
GERP RS
4.4
PromoterAI
0.055
Neutral
Varity_R
0.15
gMVP
0.57
Mutation Taster
=70/30
polymorphism

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: rs766403906; hg19: chr2-113817023; API