rs2234678

Variant names:

• chr2-113117988-A-G
• rs2234678
• ENST00000259206.9:c.-31A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000259206.9(IL1RN):​c.-31A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,357,394 control chromosomes in the GnomAD database, including 43,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4081 hom., cov: 33)
  • Exomes 𝑓: 0.25 (39308 hom.)
• Consequence: IL1RN ENST00000259206.9 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.25
• Publications: 21 publications found

Genes affected

IL1RN (HGNC:6000): (interleukin 1 receptor antagonist) The protein encoded by this gene is a member of the interleukin 1 cytokine family. This protein inhibits the activities of interleukin 1, alpha (IL1A) and interleukin 1, beta (IL1B), and modulates a variety of interleukin 1 related immune and inflammatory responses, particularly in the acute phase of infection and inflammation. This gene and five other closely related cytokine genes form a gene cluster spanning approximately 400 kb on chromosome 2. A polymorphism of this gene is reported to be associated with increased risk of osteoporotic fractures and gastric cancer. Several alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Aug 2020]

IL1RN Gene-Disease associations (from GenCC):

• sterile multifocal osteomyelitis with periostitis and pustulosis

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-113117988-A-G is Benign according to our data. Variant chr2-113117988-A-G is described in ClinVar as Benign. ClinVar VariationId is 330820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL1RN	NM_173841.3	c.-31A>G		5_prime_UTR_variant	Exon 1 of 6		NP_776213.1
IL1RN	NM_000577.5	c.-31A>G		5_prime_UTR_variant	Exon 1 of 5		NP_000568.1
IL1RN	NM_001318914.2	c.-313A>G		5_prime_UTR_variant	Exon 1 of 7		NP_001305843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL1RN	ENST00000259206.9	c.-31A>G		5_prime_UTR_variant	Exon 1 of 6	1		ENSP00000259206.5
IL1RN	ENST00000354115.6	c.-31A>G		5_prime_UTR_variant	Exon 1 of 5	1		ENSP00000329072.3
IL1RN	ENST00000361779.7	c.-250A>G		5_prime_UTR_variant	Exon 1 of 6	1		ENSP00000354816.3

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31808 AN: 152080 Hom.: 4074 Cov.: 33

Gnomad AFR AF: 0.0582

Gnomad AMI AF: 0.245

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.0973

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.230

GnomAD2 exomes AF: 0.253 AC: 63655 AN: 251438 AF XY: 0.256

Gnomad AFR exome AF: 0.0510

Gnomad AMR exome AF: 0.321

Gnomad ASJ exome AF: 0.300

Gnomad EAS exome AF: 0.0923

Gnomad FIN exome AF: 0.304

Gnomad NFE exome AF: 0.265

Gnomad OTH exome AF: 0.265

GnomAD4 exome AF: 0.248 AC: 299099 AN: 1205194 Hom.: 39308 Cov.: 17 AF XY: 0.249 AC XY: 152795 AN XY: 612620

African (AFR) AF: 0.0465 AC: 1353 AN: 29102

American (AMR) AF: 0.315 AC: 13991 AN: 44386

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 7024 AN: 24494

East Asian (EAS) AF: 0.0828 AC: 3195 AN: 38602

South Asian (SAS) AF: 0.273 AC: 22113 AN: 81086

European-Finnish (FIN) AF: 0.296 AC: 15735 AN: 53168

Middle Eastern (MID) AF: 0.210 AC: 1112 AN: 5286

European-Non Finnish (NFE) AF: 0.253 AC: 222104 AN: 877310

Other (OTH) AF: 0.241 AC: 12472 AN: 51760

GnomAD4 genome AF: 0.209 AC: 31825 AN: 152200 Hom.: 4081 Cov.: 33 AF XY: 0.212 AC XY: 15779 AN XY: 74394

African (AFR) AF: 0.0581 AC: 2415 AN: 41570

American (AMR) AF: 0.278 AC: 4253 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1019 AN: 3470

East Asian (EAS) AF: 0.0968 AC: 502 AN: 5188

South Asian (SAS) AF: 0.283 AC: 1365 AN: 4818

European-Finnish (FIN) AF: 0.304 AC: 3215 AN: 10568

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.269 AC: 18281 AN: 67972

Other (OTH) AF: 0.232 AC: 489 AN: 2112

Alfa AF: 0.251 Hom.: 5893

Bravo AF: 0.199

Asia WGS AF: 0.195 AC: 679 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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 49% of patients studied by a panel of primary immunodeficiencies. Number of patients: 47. Only high quality variants are reported. -

Sterile multifocal osteomyelitis with periostitis and pustulosis Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.86
CADD	Benign	0.39
DANN	Benign	0.71
PhyloP100		-1.3
PromoterAI		0.099	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2234678; hg19: chr2-113875565; COSMIC: COSV52080796; COSMIC: COSV52080796;