NM_012275.3:c.115+6T>C

Variant names:

• chr2-113060943-T-C
• rs148755083
• NM_012275.3:c.115+6T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 12P and 6B. PS3 PP5_Very_Strong BP4 BS1_Supporting BS2

The NM_012275.3(IL36RN):​c.115+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,608,740 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000949734: Studies have shown that this variant results in skipping of exon 3, and produces a non-functional protein and/or introduces a premature termination codon (PMID:22903787, 23698098).; SCV001142321: Experimental studies have shown that this intronic change causes skipping of exon 3, resulting in a truncated protein product (PMID:23698098; 22903787).; SCV004742886: RNA studies have shown this variant leads to skipping of exon 3 (Farooq et al. 2013. PubMed ID: 22903787).; SCV006078821: Non-canonical splice site variant demonstrated to result in loss-of-function (PMID:22903787)".

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (3 hom.)
• Consequence: IL36RN NM_012275.3 splice_region, intron
• Scores: Splicing: ADA: 0.6933
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 2.02
• Publications: 59 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: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000949734: Studies have shown that this variant results in skipping of exon 3, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 22903787, 23698098).; SCV001142321: Experimental studies have shown that this intronic change causes skipping of exon 3, resulting in a truncated protein product (PMID: 23698098; 22903787).; SCV004742886: RNA studies have shown this variant leads to skipping of exon 3 (Farooq et al. 2013. PubMed ID: 22903787).; SCV006078821: Non-canonical splice site variant demonstrated to result in loss-of-function (PMID: 22903787)
• PP5: Variant 2-113060943-T-C is Pathogenic according to our data. Variant chr2-113060943-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 40005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000342 (52/152256) while in subpopulation EAS AF = 0.01 (52/5178). AF 95% confidence interval is 0.00787. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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 3 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.115+6T>C		splice_region intron	N/A	NP_036407.1	Q9UBH0
	IL36RN	NM_173170.1		c.115+6T>C		splice_region intron	N/A	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.115+6T>C		splice_region intron	N/A	ENSP00000376896.2	Q9UBH0
	IL36RN	ENST00000346807.7	TSL:1	c.115+6T>C		splice_region intron	N/A	ENSP00000259212.3	Q9UBH0
	IL36RN	ENST00000437409.2	TSL:1	c.115+6T>C		splice_region intron	N/A	ENSP00000409262.2	Q9UBH0

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00100 AC: 252 AN: 251330 AF XY: 0.000942

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0135

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000225 AC: 327 AN: 1456484 Hom.: 3 Cov.: 29 AF XY: 0.000219 AC XY: 159 AN XY: 725028

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00749 AC: 297 AN: 39668

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107054

Other (OTH) AF: 0.000448 AC: 27 AN: 60234

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152256 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74454

African (AFR) AF: 0.00 AC: 0 AN: 41538

American (AMR) AF: 0.00 AC: 0 AN: 15298

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

East Asian (EAS) AF: 0.0100 AC: 52 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000348 Hom.: 0

Bravo AF: 0.000646

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Acrodermatitis continua suppurativa of Hallopeau (6)
3	-	-	Generalized pustular psoriasis (3)
1	-	-	Autoinflammatory syndrome (1)
1	-	-	IL36RN-related disorder (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.94
PhyloP100		2.0
Mutation Taster		=41/59	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.69
dbscSNV1_RF	Benign	0.63
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.48		Position offset: -6

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

Other links and lift over

dbSNP: rs148755083; hg19: chr2-113818520;