rs2278717

Variant names:

• chr2-113059365-A-C
• rs2278717
• NM_012275.3:c.-27-47A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_012275.3(IL36RN):​c.-27-47A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 1,547,278 control chromosomes in the GnomAD database, including 131,141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.34 (9729 hom., cov: 32)
  • Exomes 𝑓: 0.41 (121412 hom.)
• Consequence: IL36RN NM_012275.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.746
• Publications: 7 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-113059365-A-C is Benign according to our data. Variant chr2-113059365-A-C is described in ClinVar as [Benign]. Clinvar id is 2628159.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL36RN	NM_012275.3	c.-27-47A>C		intron_variant	Intron 1 of 4	ENST00000393200.7	NP_036407.1
IL36RN	NM_173170.1	c.-27-47A>C		intron_variant	Intron 1 of 4		NP_775262.1
IL36RN	XM_047443918.1	c.-27-47A>C		intron_variant	Intron 2 of 5		XP_047299874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL36RN	ENST00000393200.7	c.-27-47A>C		intron_variant	Intron 1 of 4	1	NM_012275.3	ENSP00000376896.2
IL36RN	ENST00000346807.7	c.-27-47A>C		intron_variant	Intron 1 of 4	1		ENSP00000259212.3
IL36RN	ENST00000437409.2	c.-74A>C		upstream_gene_variant		1		ENSP00000409262.2

Frequencies

GnomAD3 genomes AF: 0.343 AC: 52075 AN: 151668 Hom.: 9721 Cov.: 32

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.562

Gnomad FIN AF: 0.456

Gnomad MID AF: 0.420

Gnomad NFE AF: 0.413

Gnomad OTH AF: 0.357

GnomAD4 exome AF: 0.409 AC: 570788 AN: 1395490 Hom.: 121412 Cov.: 22 AF XY: 0.415 AC XY: 289711 AN XY: 697712

African (AFR) AF: 0.179 AC: 5819 AN: 32452

American (AMR) AF: 0.317 AC: 14025 AN: 44232

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 10409 AN: 25696

East Asian (EAS) AF: 0.184 AC: 7236 AN: 39364

South Asian (SAS) AF: 0.580 AC: 49017 AN: 84500

European-Finnish (FIN) AF: 0.448 AC: 23822 AN: 53148

Middle Eastern (MID) AF: 0.458 AC: 2259 AN: 4934

European-Non Finnish (NFE) AF: 0.414 AC: 435496 AN: 1053042

Other (OTH) AF: 0.391 AC: 22705 AN: 58122

GnomAD4 genome AF: 0.343 AC: 52112 AN: 151788 Hom.: 9729 Cov.: 32 AF XY: 0.348 AC XY: 25789 AN XY: 74192

African (AFR) AF: 0.191 AC: 7915 AN: 41450

American (AMR) AF: 0.342 AC: 5207 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1392 AN: 3468

East Asian (EAS) AF: 0.173 AC: 889 AN: 5150

South Asian (SAS) AF: 0.563 AC: 2713 AN: 4816

European-Finnish (FIN) AF: 0.456 AC: 4803 AN: 10530

Middle Eastern (MID) AF: 0.404 AC: 118 AN: 292

European-Non Finnish (NFE) AF: 0.413 AC: 28022 AN: 67836

Other (OTH) AF: 0.359 AC: 756 AN: 2108

Alfa AF: 0.381 Hom.: 33065

Bravo AF: 0.322

Asia WGS AF: 0.371 AC: 1290 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 55% of patients studied by a panel of primary immunodeficiencies. Number of patients: 53. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.7
DANN	Benign	0.44
PhyloP100		0.75
PromoterAI		-0.013	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: rs2278717; hg19: chr2-113816942; COSMIC: COSV61010335; COSMIC: COSV61010335;