2-113062953-A-G

Position:

• chr2-113062953-A-G

Variant summary

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

The NM_012275.3(IL36RN):​c.*276A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.644 in 460,014 control chromosomes in the GnomAD database, including 97,091 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 (32694 hom., cov: 31)
  • Exomes 𝑓: 0.64 (64397 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: -1.07

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=-0.99).
• BP6: Variant 2-113062953-A-G is Benign according to our data. Variant chr2-113062953-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 330784.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.78 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL36RN	NM_012275.3	c.*276A>G		3_prime_UTR_variant	5/5	ENST00000393200.7	NP_036407.1
IL36RN	NM_173170.1	c.*276A>G		3_prime_UTR_variant	5/5		NP_775262.1
IL36RN	XM_047443918.1	c.*276A>G		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.*276A>G		3_prime_UTR_variant	5/5	1	NM_012275.3	ENSP00000376896.2
IL36RN	ENST00000346807.7	c.*276A>G		3_prime_UTR_variant	5/5	1		ENSP00000259212.3
IL36RN	ENST00000514072.1	c.*49+227A>G		intron_variant		3		ENSP00000475308.1

Frequencies

GnomAD3 genomes AF: 0.653 AC: 99099 AN: 151862 Hom.: 32642 Cov.: 31

Gnomad AFR AF: 0.708

Gnomad AMI AF: 0.758

Gnomad AMR AF: 0.663

Gnomad ASJ AF: 0.688

Gnomad EAS AF: 0.708

Gnomad SAS AF: 0.800

Gnomad FIN AF: 0.630

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.601

Gnomad OTH AF: 0.685

GnomAD4 exome AF: 0.640 AC: 197193 AN: 308034 Hom.: 64397 Cov.: 2 AF XY: 0.652 AC XY: 107702 AN XY: 165140

Gnomad4 AFR exome AF: 0.700

Gnomad4 AMR exome AF: 0.680

Gnomad4 ASJ exome AF: 0.661

Gnomad4 EAS exome AF: 0.710

Gnomad4 SAS exome AF: 0.795

Gnomad4 FIN exome AF: 0.587

Gnomad4 NFE exome AF: 0.592

Gnomad4 OTH exome AF: 0.638

GnomAD4 genome AF: 0.653 AC: 99207 AN: 151980 Hom.: 32694 Cov.: 31 AF XY: 0.656 AC XY: 48740 AN XY: 74294

Gnomad4 AFR AF: 0.708

Gnomad4 AMR AF: 0.663

Gnomad4 ASJ AF: 0.688

Gnomad4 EAS AF: 0.708

Gnomad4 SAS AF: 0.801

Gnomad4 FIN AF: 0.630

Gnomad4 NFE AF: 0.601

Gnomad4 OTH AF: 0.688

Alfa AF: 0.626 Hom.: 28874

Bravo AF: 0.658

Asia WGS AF: 0.790 AC: 2741 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 rs1800930 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	-0.99
CADD	Benign	1.4
DANN	Benign	0.38

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: rs1800930; hg19: chr2-113820530;