chr2-113117936-G-A

Position:

• chr2-113117936-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000259206.9(IL1RN):​c.-83G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00714 in 853,512 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0055 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0075 (39 hom.)
• Consequence: IL1RN ENST00000259206.9 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.870

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-113117936-G-A is Benign according to our data. Variant chr2-113117936-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 330818.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-113117936-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00551 (839/152320) while in subpopulation NFE AF= 0.00901 (613/68032). AF 95% confidence interval is 0.00842. There are 4 homozygotes in gnomad4. There are 391 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL1RN	XM_011511121.2	c.-272-2130G>A		intron_variant
IL1RN	XM_047444184.1	c.-272-2130G>A		intron_variant
IL1RN	XM_047444185.1	c.-273+271G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL1RN	ENST00000259206.9	c.-83G>A		5_prime_UTR_variant	1/6	1
IL1RN	ENST00000354115.6	c.-83G>A		5_prime_UTR_variant	1/5	1		A1
IL1RN	ENST00000361779.7	c.-302G>A		5_prime_UTR_variant	1/6	1

Frequencies

GnomAD3 genomes AF: 0.00551 AC: 839 AN: 152202 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00901

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.00749 AC: 5252 AN: 701192 Hom.: 39 Cov.: 9 AF XY: 0.00716 AC XY: 2704 AN XY: 377526

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00429

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00138

Gnomad4 FIN exome AF: 0.0103

Gnomad4 NFE exome AF: 0.0101

Gnomad4 OTH exome AF: 0.00582

GnomAD4 genome AF: 0.00551 AC: 839 AN: 152320 Hom.: 4 Cov.: 33 AF XY: 0.00525 AC XY: 391 AN XY: 74490

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.0107

Gnomad4 NFE AF: 0.00901

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00746 Hom.: 0

Bravo AF: 0.00476

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Sterile multifocal osteomyelitis with periostitis and pustulosis Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	13
DANN	Benign	0.68

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs45526933; hg19: chr2-113875513;