rs423904

Variant names:

• chr2-113129685-C-T
• rs423904
• ENST00000472292.1:n.275C>T

Variant summary

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

The ENST00000472292.1(IL1RN):​n.275C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,516,674 control chromosomes in the GnomAD database, including 54,265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4293 hom., cov: 32)
  • Exomes 𝑓: 0.27 (49972 hom.)
• Consequence: IL1RN ENST00000472292.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.612
• Publications: 13 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=-0.87).
• BP6: Variant 2-113129685-C-T is Benign according to our data. Variant chr2-113129685-C-T is described in ClinVar as Benign. ClinVar VariationId is 1294767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL1RN	NM_173842.3	c.205+21C>T		intron_variant	Intron 2 of 3	ENST00000409930.4	NP_776214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL1RN	ENST00000409930.4	c.205+21C>T		intron_variant	Intron 2 of 3	1	NM_173842.3	ENSP00000387173.3

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32842 AN: 152058 Hom.: 4285 Cov.: 32

Gnomad AFR AF: 0.0705

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.0772

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.239

GnomAD2 exomes AF: 0.256 AC: 64384 AN: 251162 AF XY: 0.259

Gnomad AFR exome AF: 0.0652

Gnomad AMR exome AF: 0.321

Gnomad ASJ exome AF: 0.298

Gnomad EAS exome AF: 0.0708

Gnomad FIN exome AF: 0.305

Gnomad NFE exome AF: 0.273

Gnomad OTH exome AF: 0.266

GnomAD4 exome AF: 0.265 AC: 362245 AN: 1364498 Hom.: 49972 Cov.: 22 AF XY: 0.265 AC XY: 181650 AN XY: 684408

African (AFR) AF: 0.0629 AC: 1988 AN: 31628

American (AMR) AF: 0.317 AC: 14144 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 7394 AN: 25536

East Asian (EAS) AF: 0.0598 AC: 2350 AN: 39290

South Asian (SAS) AF: 0.280 AC: 23603 AN: 84204

European-Finnish (FIN) AF: 0.300 AC: 15980 AN: 53338

Middle Eastern (MID) AF: 0.217 AC: 1219 AN: 5610

European-Non Finnish (NFE) AF: 0.275 AC: 281061 AN: 1023166

Other (OTH) AF: 0.254 AC: 14506 AN: 57128

GnomAD4 genome AF: 0.216 AC: 32880 AN: 152176 Hom.: 4293 Cov.: 32 AF XY: 0.219 AC XY: 16280 AN XY: 74396

African (AFR) AF: 0.0709 AC: 2944 AN: 41548

American (AMR) AF: 0.283 AC: 4331 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1008 AN: 3468

East Asian (EAS) AF: 0.0766 AC: 397 AN: 5180

South Asian (SAS) AF: 0.289 AC: 1393 AN: 4818

European-Finnish (FIN) AF: 0.305 AC: 3227 AN: 10570

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

European-Non Finnish (NFE) AF: 0.276 AC: 18783 AN: 67988

Other (OTH) AF: 0.241 AC: 508 AN: 2112

Alfa AF: 0.252 Hom.: 14366

Bravo AF: 0.206

Asia WGS AF: 0.196 AC: 682 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

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 51% of patients studied by a panel of primary immunodeficiencies. Number of patients: 49. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.1
DANN	Benign	0.60
PhyloP100		-0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs423904; hg19: chr2-113887262; COSMIC: COSV52080072;