rs878972

chr2-113120136-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000259206.9(IL1RN):c.73+8A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,604,640 control chromosomes in the GnomAD database, including 56,618 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4070 hom., cov: 30)
  • Exomes 𝑓: 0.26 (52548 hom.)
• Consequence: IL1RN ENST00000259206.9 splice_region, intron
• Scores: Splicing: ADA: 0.00002619
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.149

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 2-113120136-A-C is Benign according to our data. Variant chr2-113120136-A-C is described in ClinVar as [Benign]. Clinvar id is 330822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-113120136-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL1RN	NM_000577.5	c.10+2108A>C		intron_variant
IL1RN	NM_001318914.2	c.-210+8A>C		splice_region_variant, intron_variant
IL1RN	NM_173841.3	c.73+8A>C		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL1RN	ENST00000259206.9	c.73+8A>C		splice_region_variant, intron_variant		1
IL1RN	ENST00000354115.6	c.10+2108A>C		intron_variant		1		A1
IL1RN	ENST00000361779.7	c.-209-1312A>C		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31746 AN: 151264 Hom.: 4064 Cov.: 30

Gnomad AFR AF: 0.0610

Gnomad AMI AF: 0.244

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.303

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.229

GnomAD3 exomes AF: 0.253 AC: 63662 AN: 251238 Hom.: 9001 AF XY: 0.256 AC XY: 34830 AN XY: 135800

Gnomad AFR exome AF: 0.0536

Gnomad AMR exome AF: 0.317

Gnomad ASJ exome AF: 0.295

Gnomad EAS exome AF: 0.0945

Gnomad SAS exome AF: 0.285

Gnomad FIN exome AF: 0.304

Gnomad NFE exome AF: 0.266

Gnomad OTH exome AF: 0.266

GnomAD4 exome AF: 0.263 AC: 382285 AN: 1453256 Hom.: 52548 Cov.: 29 AF XY: 0.263 AC XY: 190375 AN XY: 723634

Gnomad4 AFR exome AF: 0.0499

Gnomad4 AMR exome AF: 0.313

Gnomad4 ASJ exome AF: 0.287

Gnomad4 EAS exome AF: 0.101

Gnomad4 SAS exome AF: 0.282

Gnomad4 FIN exome AF: 0.298

Gnomad4 NFE exome AF: 0.270

Gnomad4 OTH exome AF: 0.252

GnomAD4 genome AF: 0.210 AC: 31763 AN: 151384 Hom.: 4070 Cov.: 30 AF XY: 0.212 AC XY: 15694 AN XY: 73864

Gnomad4 AFR AF: 0.0609

Gnomad4 AMR AF: 0.275

Gnomad4 ASJ AF: 0.286

Gnomad4 EAS AF: 0.104

Gnomad4 SAS AF: 0.288

Gnomad4 FIN AF: 0.303

Gnomad4 NFE AF: 0.269

Gnomad4 OTH AF: 0.231

Alfa AF: 0.238 Hom.: 2183

Bravo AF: 0.199

Asia WGS AF: 0.202 AC: 703 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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 -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	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:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	5.0
Dann	Benign	0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs878972; hg19: chr2-113877713; COSMIC: COSV52080718; COSMIC: COSV52080718;