2-113118007-G-C

Variant names:

• chr2-113118007-G-C
• rs2234679
• ENST00000259206.9:c.-12G>C

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.-12G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,519,538 control chromosomes in the GnomAD database, including 50,468 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4082 hom., cov: 33)
  • Exomes 𝑓: 0.25 (46386 hom.)
• Consequence: IL1RN ENST00000259206.9 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.323
• Publications: 17 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=-0.88).
• BP6: Variant 2-113118007-G-C is Benign according to our data. Variant chr2-113118007-G-C is described in ClinVar as Benign. ClinVar VariationId is 330821.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.-12G>C		5_prime_UTR_variant	Exon 1 of 6		NP_776213.1
IL1RN	NM_000577.5	c.-12G>C		5_prime_UTR_variant	Exon 1 of 5		NP_000568.1
IL1RN	NM_001318914.2	c.-294G>C		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.-12G>C		5_prime_UTR_variant	Exon 1 of 6	1		ENSP00000259206.5
IL1RN	ENST00000354115.6	c.-12G>C		5_prime_UTR_variant	Exon 1 of 5	1		ENSP00000329072.3
IL1RN	ENST00000361779.7	c.-231G>C		5_prime_UTR_variant	Exon 1 of 6	1		ENSP00000354816.3

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31816 AN: 152078 Hom.: 4075 Cov.: 33

Gnomad AFR AF: 0.0583

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.293

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: 63662 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: 0.0924

Gnomad FIN exome AF: 0.304

Gnomad NFE exome AF: 0.265

Gnomad OTH exome AF: 0.265

GnomAD4 exome AF: 0.253 AC: 345495 AN: 1367340 Hom.: 46386 Cov.: 22 AF XY: 0.254 AC XY: 173843 AN XY: 685680

African (AFR) AF: 0.0455 AC: 1465 AN: 32178

American (AMR) AF: 0.315 AC: 14041 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 7319 AN: 25506

East Asian (EAS) AF: 0.0828 AC: 3256 AN: 39320

South Asian (SAS) AF: 0.275 AC: 23141 AN: 84262

European-Finnish (FIN) AF: 0.296 AC: 15758 AN: 53216

Middle Eastern (MID) AF: 0.212 AC: 1187 AN: 5590

European-Non Finnish (NFE) AF: 0.259 AC: 265421 AN: 1025598

Other (OTH) AF: 0.243 AC: 13907 AN: 57118

GnomAD4 genome AF: 0.209 AC: 31833 AN: 152198 Hom.: 4082 Cov.: 33 AF XY: 0.212 AC XY: 15787 AN XY: 74408

African (AFR) AF: 0.0582 AC: 2419 AN: 41562

American (AMR) AF: 0.278 AC: 4249 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1017 AN: 3470

East Asian (EAS) AF: 0.0968 AC: 502 AN: 5186

South Asian (SAS) AF: 0.283 AC: 1363 AN: 4810

European-Finnish (FIN) AF: 0.304 AC: 3222 AN: 10586

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

European-Non Finnish (NFE) AF: 0.269 AC: 18285 AN: 67984

Other (OTH) AF: 0.232 AC: 489 AN: 2110

Alfa AF: 0.246 Hom.: 1014

Bravo AF: 0.199

Asia WGS AF: 0.195 AC: 679 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sterile multifocal osteomyelitis with periostitis and pustulosis Benign:1

Jan 12, 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	-0.88
CADD	Benign	6.0
DANN	Benign	0.80
PhyloP100		-0.32
PromoterAI		-0.050	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2234679; hg19: chr2-113875584; COSMIC: COSV52080803; COSMIC: COSV52080803;