chr2-113062899-T-C

Variant names:

• chr2-113062899-T-C
• rs2515401
• NM_012275.3:c.*222T>C

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.*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
• Publications: 13 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: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• 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=-0.98).
• 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 VariationId is 330783.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.781 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL36RN	NM_012275.3	MANE Select	c.*222T>C		3_prime_UTR	Exon 5 of 5	NP_036407.1	Q9UBH0
	IL36RN	NM_173170.1		c.*222T>C		3_prime_UTR	Exon 5 of 5	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.*222T>C		3_prime_UTR	Exon 5 of 5	ENSP00000376896.2	Q9UBH0
	IL36RN	ENST00000346807.7	TSL:1	c.*222T>C		3_prime_UTR	Exon 5 of 5	ENSP00000259212.3	Q9UBH0
	IL36RN	ENST00000514072.1	TSL:3	c.*49+173T>C		intron	N/A	ENSP00000475308.1	U3KPW9

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

African (AFR) AF: 0.712 AC: 8881 AN: 12472

American (AMR) AF: 0.698 AC: 14659 AN: 20998

Ashkenazi Jewish (ASJ) AF: 0.674 AC: 9136 AN: 13552

East Asian (EAS) AF: 0.729 AC: 21230 AN: 29114

South Asian (SAS) AF: 0.797 AC: 37491 AN: 47058

European-Finnish (FIN) AF: 0.606 AC: 16239 AN: 26776

Middle Eastern (MID) AF: 0.741 AC: 1414 AN: 1908

European-Non Finnish (NFE) AF: 0.603 AC: 156877 AN: 259982

Other (OTH) AF: 0.651 AC: 16282 AN: 25028

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

African (AFR) AF: 0.707 AC: 29308 AN: 41442

American (AMR) AF: 0.664 AC: 10145 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 2386 AN: 3470

East Asian (EAS) AF: 0.707 AC: 3655 AN: 5170

South Asian (SAS) AF: 0.802 AC: 3863 AN: 4818

European-Finnish (FIN) AF: 0.629 AC: 6654 AN: 10576

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

European-Non Finnish (NFE) AF: 0.601 AC: 40829 AN: 67960

Other (OTH) AF: 0.689 AC: 1453 AN: 2110

Alfa AF: 0.625 Hom.: 37045

Bravo AF: 0.658

Asia WGS AF: 0.790 AC: 2743 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	-0.98
CADD	Benign	0.34
DANN	Benign	0.42
PhyloP100		-2.8
PromoterAI		-0.026	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: rs2515401; hg19: chr2-113820476;