2-112984946-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_019618.4(IL36G):​c.407C>T​(p.Pro136Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,614,022 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 1 hom. )

Consequence

IL36G
NM_019618.4 missense

Scores

3
6
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.16
Variant links:
Genes affected
IL36G (HGNC:15741): (interleukin 36 gamma) The protein encoded by this gene is a member of the interleukin 1 cytokine family. The activity of this cytokine is mediated by interleukin 1 receptor-like 2 (IL1RL2/IL1R-rp2), and is specifically inhibited by interleukin 1 family, member 5 (IL1F5/IL-1 delta). Interferon-gamma, tumor necrosis factor-alpha and interleukin 1, beta (IL1B) are reported to stimulate the expression of this cytokine in keratinocytes. The expression of this cytokine in keratinocytes can also be induced by a contact hypersensitivity reaction or herpes simplex virus infection. This gene and eight other interleukin 1 family genes form a cytokine gene cluster on chromosome 2. [provided by RefSeq, May 2019]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IL36GNM_019618.4 linkc.407C>T p.Pro136Leu missense_variant Exon 5 of 5 ENST00000259205.5 NP_062564.1 Q9NZH8-1
IL36GNM_001278568.2 linkc.302C>T p.Pro101Leu missense_variant Exon 4 of 4 NP_001265497.1 Q9NZH8-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IL36GENST00000259205.5 linkc.407C>T p.Pro136Leu missense_variant Exon 5 of 5 1 NM_019618.4 ENSP00000259205.3 Q9NZH8-1
IL36GENST00000376489.6 linkc.302C>T p.Pro101Leu missense_variant Exon 4 of 4 1 ENSP00000365672.2 Q9NZH8-2

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152088
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000966
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000796
AC:
20
AN:
251410
Hom.:
1
AF XY:
0.0000810
AC XY:
11
AN XY:
135874
show subpopulations
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:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000141
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000226
AC:
33
AN:
1461814
Hom.:
1
Cov.:
31
AF XY:
0.0000220
AC XY:
16
AN XY:
727214
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000198
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152208
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74436
show subpopulations
Gnomad4 AFR
AF:
0.0000963
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.000140
AC:
17
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 21, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.407C>T (p.P136L) alteration is located in exon 5 (coding exon 4) of the IL36G gene. This alteration results from a C to T substitution at nucleotide position 407, causing the proline (P) at amino acid position 136 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.30
BayesDel_addAF
Benign
-0.073
T
BayesDel_noAF
Benign
-0.090
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.21
.;T
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Benign
0.75
D
LIST_S2
Benign
0.82
T;T
M_CAP
Benign
0.029
D
MetaRNN
Pathogenic
0.92
D;D
MetaSVM
Benign
-0.39
T
MutationAssessor
Pathogenic
3.2
.;M
PrimateAI
Uncertain
0.51
T
PROVEAN
Pathogenic
-9.9
D;D
REVEL
Benign
0.29
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0070
D;D
Polyphen
1.0
D;D
Vest4
0.67
MutPred
0.85
.;Gain of catalytic residue at P136 (P = 0.0045);
MVP
0.33
MPC
0.42
ClinPred
1.0
D
GERP RS
4.4
Varity_R
0.83
gMVP
0.77

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs549223824; hg19: chr2-113742523; API