2-113129758-T-G

Variant names:

• chr2-113129758-T-G
• rs2232354
• ENST00000472292.1:n.348T>G

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.348T>G 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 0.182 in 846,010 control chromosomes in the GnomAD database, including 15,930 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2101 hom., cov: 33)
  • Exomes 𝑓: 0.19 (13829 hom.)
• Consequence: IL1RN ENST00000472292.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0250
• 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=-0.82).
• BP6: Variant 2-113129758-T-G is Benign according to our data. Variant chr2-113129758-T-G is described in ClinVar as Benign. ClinVar VariationId is 1248659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL1RN	NM_173842.3	c.205+94T>G		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+94T>G		intron_variant	Intron 2 of 3	1	NM_173842.3	ENSP00000387173.3

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22101 AN: 152112 Hom.: 2099 Cov.: 33

Gnomad AFR AF: 0.0375

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.0397

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.179

GnomAD4 exome AF: 0.190 AC: 131920 AN: 693780 Hom.: 13829 Cov.: 9 AF XY: 0.195 AC XY: 72822 AN XY: 373470

African (AFR) AF: 0.0381 AC: 722 AN: 18930

American (AMR) AF: 0.185 AC: 7916 AN: 42878

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 4463 AN: 21208

East Asian (EAS) AF: 0.0363 AC: 1311 AN: 36116

South Asian (SAS) AF: 0.245 AC: 17280 AN: 70394

European-Finnish (FIN) AF: 0.156 AC: 8121 AN: 52140

Middle Eastern (MID) AF: 0.322 AC: 1376 AN: 4272

European-Non Finnish (NFE) AF: 0.204 AC: 84233 AN: 412708

Other (OTH) AF: 0.185 AC: 6498 AN: 35134

GnomAD4 genome AF: 0.145 AC: 22111 AN: 152230 Hom.: 2101 Cov.: 33 AF XY: 0.144 AC XY: 10740 AN XY: 74434

African (AFR) AF: 0.0374 AC: 1553 AN: 41562

American (AMR) AF: 0.180 AC: 2759 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 745 AN: 3470

East Asian (EAS) AF: 0.0400 AC: 207 AN: 5180

South Asian (SAS) AF: 0.223 AC: 1074 AN: 4824

European-Finnish (FIN) AF: 0.150 AC: 1588 AN: 10598

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.199 AC: 13547 AN: 67986

Other (OTH) AF: 0.183 AC: 387 AN: 2114

Alfa AF: 0.173 Hom.: 4833

Bravo AF: 0.143

Asia WGS AF: 0.143 AC: 498 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 29% of patients studied by a panel of primary immunodeficiencies. Number of patients: 28. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.6
DANN	Benign	0.42
PhyloP100		-0.025
Mutation Taster		=8/92	disease causing

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: rs2232354; hg19: chr2-113887335; COSMIC: COSV52080733;