2-113117932-G-C

Variant names:

• chr2-113117932-G-C
• rs2234677
• ENST00000259206.9:c.-87G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000259206.9(IL1RN):​c.-87G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 686,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: IL1RN ENST00000259206.9 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.267
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL1RN	XM_011511121.2	c.-272-2134G>C		intron_variant	Intron 3 of 8		XP_011509423.1
IL1RN	XM_047444184.1	c.-272-2134G>C		intron_variant	Intron 4 of 9		XP_047300140.1
IL1RN	XM_047444185.1	c.-273+267G>C		intron_variant	Intron 4 of 9		XP_047300141.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL1RN	ENST00000259206.9	c.-87G>C		5_prime_UTR_variant	Exon 1 of 6	1		ENSP00000259206.5
IL1RN	ENST00000354115.6	c.-87G>C		5_prime_UTR_variant	Exon 1 of 5	1		ENSP00000329072.3
IL1RN	ENST00000361779.7	c.-306G>C		5_prime_UTR_variant	Exon 1 of 6	1		ENSP00000354816.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000146 AC: 1 AN: 686756 Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0 AN XY: 370540

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 18872

American (AMR) AF: 0.00 AC: 0 AN: 43760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21344

East Asian (EAS) AF: 0.00 AC: 0 AN: 36348

South Asian (SAS) AF: 0.00 AC: 0 AN: 70832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3326

European-Non Finnish (NFE) AF: 0.00000247 AC: 1 AN: 404370

Other (OTH) AF: 0.00 AC: 0 AN: 34904

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.7
DANN	Benign	0.66
PhyloP100		-0.27
PromoterAI		-0.0020	Neutral

Splicing

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

Other links and lift over

dbSNP: rs2234677; hg19: chr2-113875509;