rs139497891

Variant names:

• chr2-113062235-C-T
• rs139497891
• NM_012275.3:c.227C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 5P and 5B. PS3 PP5 BP4 BS2

The NM_012275.3(IL36RN):​c.227C>T​(p.Pro76Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,613,982 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000915853: In vitro analysis in HEK293T cells did not detect any IL-36Ra protein and found no reduction in NF-kB activity which is repressed in wildtype in association with the p.Pro76Leu variant (Tauber et al. 2016)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P76P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: IL36RN NM_012275.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2
• Conservation: PhyloP100: 2.64
• Publications: 29 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000915853: In vitro analysis in HEK293T cells did not detect any IL-36Ra protein and found no reduction in NF-kB activity which is repressed in wildtype in association with the p.Pro76Leu variant (Tauber et al. 2016).; SCV005418202: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."
• PP5: Variant 2-113062235-C-T is Pathogenic according to our data. Variant chr2-113062235-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 575254.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19842246). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR 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.227C>T	p.Pro76Leu	missense	Exon 4 of 5	NP_036407.1	Q9UBH0
	IL36RN	NM_173170.1		c.227C>T	p.Pro76Leu	missense	Exon 4 of 5	NP_775262.1	Q9UBH0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL36RN	ENST00000393200.7	TSL:1 MANE Select	c.227C>T	p.Pro76Leu	missense	Exon 4 of 5	ENSP00000376896.2	Q9UBH0
	IL36RN	ENST00000346807.7	TSL:1	c.227C>T	p.Pro76Leu	missense	Exon 4 of 5	ENSP00000259212.3	Q9UBH0
	IL36RN	ENST00000437409.2	TSL:1	c.227C>T	p.Pro76Leu	missense	Exon 3 of 4	ENSP00000409262.2	Q9UBH0

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152046 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000287 AC: 72 AN: 251288 AF XY: 0.000309

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000924

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000241 AC: 352 AN: 1461818 Hom.: 2 Cov.: 32 AF XY: 0.000254 AC XY: 185 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000605 AC: 24 AN: 39700

South Asian (SAS) AF: 0.000649 AC: 56 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.000221 AC: 246 AN: 1111984

Other (OTH) AF: 0.000331 AC: 20 AN: 60392

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74396

African (AFR) AF: 0.00 AC: 0 AN: 41528

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5174

South Asian (SAS) AF: 0.000832 AC: 4 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.000470 Hom.: 0

Bravo AF: 0.000200

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000329 AC: 40

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	Generalized pustular psoriasis (3)
2	-	-	Acrodermatitis continua suppurativa of Hallopeau (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		2.6
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.58
Sift	Benign	0.16	T
Sift4G	Benign	0.076	T
Polyphen		1.0	D
Vest4		0.71
MVP		0.80
MPC		0.53
ClinPred		0.35	T
GERP RS		5.2
PromoterAI		-0.012	Neutral
Varity_R		0.32
gMVP		0.84
Mutation Taster		=76/24	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs139497891; hg19: chr2-113819812;