2-113132727-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_173842.3(IL1RN):c.390T>C(p.Ser130=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 1,614,016 control chromosomes in the GnomAD database, including 77,305 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9538 hom., cov: 33)
  • Exomes 𝑓: 0.29 (67767 hom.)
• Consequence: IL1RN NM_173842.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.15

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-113132727-T-C is Benign according to our data. Variant chr2-113132727-T-C is described in ClinVar as [Benign]. Clinvar id is 330827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL1RN	NM_173842.3	c.390T>C	p.Ser130=	synonymous_variant	4/4	ENST00000409930.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL1RN	ENST00000409930.4	c.390T>C	p.Ser130=	synonymous_variant	4/4	1	NM_173842.3	P4

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51496 AN: 152098 Hom.: 9523 Cov.: 33

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.336

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.588

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.282

GnomAD3 exomes AF: 0.305 AC: 76749 AN: 251324 Hom.: 13280 AF XY: 0.294 AC XY: 39936 AN XY: 135834

Gnomad AFR exome AF: 0.438

Gnomad AMR exome AF: 0.237

Gnomad ASJ exome AF: 0.208

Gnomad EAS exome AF: 0.593

Gnomad SAS exome AF: 0.141

Gnomad FIN exome AF: 0.420

Gnomad NFE exome AF: 0.293

Gnomad OTH exome AF: 0.286

GnomAD4 exome AF: 0.294 AC: 430010 AN: 1461800 Hom.: 67767 Cov.: 37 AF XY: 0.289 AC XY: 210490 AN XY: 727216

Gnomad4 AFR exome AF: 0.438

Gnomad4 AMR exome AF: 0.239

Gnomad4 ASJ exome AF: 0.211

Gnomad4 EAS exome AF: 0.619

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.418

Gnomad4 NFE exome AF: 0.288

Gnomad4 OTH exome AF: 0.298

GnomAD4 genome AF: 0.339 AC: 51534 AN: 152216 Hom.: 9538 Cov.: 33 AF XY: 0.339 AC XY: 25261 AN XY: 74420

Gnomad4 AFR AF: 0.433

Gnomad4 AMR AF: 0.236

Gnomad4 ASJ AF: 0.207

Gnomad4 EAS AF: 0.588

Gnomad4 SAS AF: 0.146

Gnomad4 FIN AF: 0.417

Gnomad4 NFE AF: 0.296

Gnomad4 OTH AF: 0.281

Alfa AF: 0.296 Hom.: 17950

Bravo AF: 0.334

Asia WGS AF: 0.347 AC: 1206 AN: 3478

EpiCase AF: 0.277

EpiControl AF: 0.274

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sterile multifocal osteomyelitis with periostitis and pustulosis Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

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, 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 48% of patients studied by a panel of primary immunodeficiencies. Number of patients: 46. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.16
Dann	Benign	0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs315952; hg19: chr2-113890304; COSMIC: COSV52081886; COSMIC: COSV52081886;