2-113062899-T-C

Position:

• chr2-113062899-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_012275.3(IL36RN):​c.*222T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 588,930 control chromosomes in the GnomAD database, including 125,218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.65 (32678 hom., cov: 32)
  • Exomes 𝑓: 0.65 (92540 hom.)
• Consequence: IL36RN NM_012275.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -2.79

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 2-113062899-T-C is Benign according to our data. Variant chr2-113062899-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 330783.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL36RN	NM_012275.3	c.*222T>C		3_prime_UTR_variant	5/5	ENST00000393200.7	NP_036407.1
IL36RN	NM_173170.1	c.*222T>C		3_prime_UTR_variant	5/5		NP_775262.1
IL36RN	XM_047443918.1	c.*222T>C		3_prime_UTR_variant	6/6		XP_047299874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL36RN	ENST00000393200.7	c.*222T>C		3_prime_UTR_variant	5/5	1	NM_012275.3	ENSP00000376896	P1
IL36RN	ENST00000346807.7	c.*222T>C		3_prime_UTR_variant	5/5	1		ENSP00000259212	P1
IL36RN	ENST00000514072.1	c.*49+173T>C		intron_variant		3		ENSP00000475308

Frequencies

GnomAD3 genomes AF: 0.652 AC: 99091 AN: 151924 Hom.: 32625 Cov.: 32

Gnomad AFR AF: 0.707

Gnomad AMI AF: 0.757

Gnomad AMR AF: 0.663

Gnomad ASJ AF: 0.688

Gnomad EAS AF: 0.708

Gnomad SAS AF: 0.801

Gnomad FIN AF: 0.629

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.601

Gnomad OTH AF: 0.685

GnomAD4 exome AF: 0.646 AC: 282209 AN: 436888 Hom.: 92540 Cov.: 3 AF XY: 0.655 AC XY: 151507 AN XY: 231354

Gnomad4 AFR exome AF: 0.712

Gnomad4 AMR exome AF: 0.698

Gnomad4 ASJ exome AF: 0.674

Gnomad4 EAS exome AF: 0.729

Gnomad4 SAS exome AF: 0.797

Gnomad4 FIN exome AF: 0.606

Gnomad4 NFE exome AF: 0.603

Gnomad4 OTH exome AF: 0.651

GnomAD4 genome AF: 0.652 AC: 99200 AN: 152042 Hom.: 32678 Cov.: 32 AF XY: 0.656 AC XY: 48748 AN XY: 74350

Gnomad4 AFR AF: 0.707

Gnomad4 AMR AF: 0.664

Gnomad4 ASJ AF: 0.688

Gnomad4 EAS AF: 0.707

Gnomad4 SAS AF: 0.802

Gnomad4 FIN AF: 0.629

Gnomad4 NFE AF: 0.601

Gnomad4 OTH AF: 0.689

Alfa AF: 0.619 Hom.: 27860

Bravo AF: 0.658

Asia WGS AF: 0.790 AC: 2743 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Acrodermatitis continua suppurativa of Hallopeau Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Patients with Generalized pustular Psoriasis, with certain mutations, respond very well to IL-1 antagonists like Anakinra, as IL36RN mutations upregulate IL-1. IL36RN gene encodes IL-36 receptor antagonist (IL-36Ra), which is required for subsequent activation of intracellular NF-κB and mitogen-activated protein kinase pathways. However, the role of rs2515401 is yet to be ascertained. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Generalized pustular psoriasis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.34
DANN	Benign	0.42

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

Other links and lift over

dbSNP: rs2515401; hg19: chr2-113820476;