2-113059450-TG-T

Variant names:

• chr2-113059450-TG-T
• NM_012275.3:c.16delG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_012275.3(IL36RN):​c.16delG​(p.Ala6ArgfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IL36RN NM_012275.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.78

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-113059450-TG-T is Pathogenic according to our data. Variant chr2-113059450-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 3640207.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL36RN	NM_012275.3	c.16delG	p.Ala6ArgfsTer6	frameshift_variant	Exon 2 of 5	ENST00000393200.7	NP_036407.1
IL36RN	NM_173170.1	c.16delG	p.Ala6ArgfsTer6	frameshift_variant	Exon 2 of 5		NP_775262.1
IL36RN	XM_047443918.1	c.16delG	p.Ala6ArgfsTer6	frameshift_variant	Exon 3 of 6		XP_047299874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL36RN	ENST00000393200.7	c.16delG	p.Ala6ArgfsTer6	frameshift_variant	Exon 2 of 5	1	NM_012275.3	ENSP00000376896.2
IL36RN	ENST00000346807.7	c.16delG	p.Ala6ArgfsTer6	frameshift_variant	Exon 2 of 5	1		ENSP00000259212.3
IL36RN	ENST00000437409.2	c.16delG	p.Ala6ArgfsTer6	frameshift_variant	Exon 1 of 4	1		ENSP00000409262.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Generalized pustular psoriasis Pathogenic:1

Mar 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ala6Argfs*6) in the IL36RN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IL36RN are known to be pathogenic (PMID: 23698098). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IL36RN-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-113817027;