2-113062953-A-G

Variant names:

• chr2-113062953-A-G
• rs1800930
• NM_012275.3:c.*276A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 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: Orphanet, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• pustulosis palmaris et plantaris

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 330784.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.78 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL36RN	NM_012275.3	MANE Select	c.*276A>G		3_prime_UTR	Exon 5 of 5	NP_036407.1
	IL36RN	NM_173170.1		c.*276A>G		3_prime_UTR	Exon 5 of 5	NP_775262.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL36RN	ENST00000393200.7	TSL:1 MANE Select	c.*276A>G		3_prime_UTR	Exon 5 of 5	ENSP00000376896.2
	IL36RN	ENST00000346807.7	TSL:1	c.*276A>G		3_prime_UTR	Exon 5 of 5	ENSP00000259212.3
	IL36RN	ENST00000514072.1	TSL:3	c.*49+227A>G		intron	N/A	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

African (AFR) AF: 0.700 AC: 6245 AN: 8918

American (AMR) AF: 0.680 AC: 10066 AN: 14802

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 5870 AN: 8884

East Asian (EAS) AF: 0.710 AC: 12315 AN: 17334

South Asian (SAS) AF: 0.795 AC: 35235 AN: 44324

European-Finnish (FIN) AF: 0.587 AC: 8932 AN: 15214

Middle Eastern (MID) AF: 0.734 AC: 910 AN: 1240

European-Non Finnish (NFE) AF: 0.592 AC: 106770 AN: 180324

Other (OTH) AF: 0.638 AC: 10850 AN: 16994

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

African (AFR) AF: 0.708 AC: 29321 AN: 41422

American (AMR) AF: 0.663 AC: 10140 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 2389 AN: 3470

East Asian (EAS) AF: 0.708 AC: 3658 AN: 5168

South Asian (SAS) AF: 0.801 AC: 3866 AN: 4824

European-Finnish (FIN) AF: 0.630 AC: 6654 AN: 10560

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.601 AC: 40819 AN: 67936

Other (OTH) AF: 0.688 AC: 1455 AN: 2114

Alfa AF: 0.630 Hom.: 38612

Bravo AF: 0.658

Asia WGS AF: 0.790 AC: 2741 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.4
DANN	Benign	0.38
PhyloP100		-1.1
PromoterAI		0.012	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800930; hg19: chr2-113820530;