rs4251969

Variant names:

• chr2-113118176-C-G
• rs4251969
• ENST00000259206.9:c.10+148C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173841.3(IL1RN):​c.10+148C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 1,262,988 control chromosomes in the GnomAD database, including 41,060 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4051 hom., cov: 33)
  • Exomes 𝑓: 0.25 (37009 hom.)
• Consequence: IL1RN NM_173841.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.300
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, 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 2-113118176-C-G is Benign according to our data. Variant chr2-113118176-C-G is described in ClinVar as Benign. ClinVar VariationId is 1258566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173841.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL1RN	NM_173841.3		c.10+148C>G		intron	N/A	NP_776213.1	P18510-3
	IL1RN	NM_000577.5		c.10+148C>G		intron	N/A	NP_000568.1	P18510-2
	IL1RN	NM_001318914.2		c.-273+148C>G		intron	N/A	NP_001305843.1	P18510-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL1RN	ENST00000259206.9	TSL:1	c.10+148C>G		intron	N/A	ENSP00000259206.5	P18510-3
	IL1RN	ENST00000354115.6	TSL:1	c.10+148C>G		intron	N/A	ENSP00000329072.3	P18510-2
	IL1RN	ENST00000361779.7	TSL:1	c.-210+148C>G		intron	N/A	ENSP00000354816.3	P18510-4

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31756 AN: 151988 Hom.: 4045 Cov.: 33

Gnomad AFR AF: 0.0584

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.292

Gnomad EAS AF: 0.0971

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.303

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.231

GnomAD4 exome AF: 0.248 AC: 275516 AN: 1110882 Hom.: 37009 AF XY: 0.249 AC XY: 140399 AN XY: 563472

African (AFR) AF: 0.0459 AC: 1244 AN: 27106

American (AMR) AF: 0.312 AC: 11840 AN: 37982

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 6571 AN: 23158

East Asian (EAS) AF: 0.0812 AC: 2945 AN: 36248

South Asian (SAS) AF: 0.271 AC: 20512 AN: 75584

European-Finnish (FIN) AF: 0.284 AC: 11026 AN: 38860

Middle Eastern (MID) AF: 0.208 AC: 1069 AN: 5130

European-Non Finnish (NFE) AF: 0.255 AC: 208524 AN: 817748

Other (OTH) AF: 0.240 AC: 11785 AN: 49066

GnomAD4 genome AF: 0.209 AC: 31771 AN: 152106 Hom.: 4051 Cov.: 33 AF XY: 0.212 AC XY: 15741 AN XY: 74344

African (AFR) AF: 0.0582 AC: 2419 AN: 41550

American (AMR) AF: 0.278 AC: 4249 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 1013 AN: 3466

East Asian (EAS) AF: 0.0966 AC: 500 AN: 5178

South Asian (SAS) AF: 0.283 AC: 1367 AN: 4824

European-Finnish (FIN) AF: 0.303 AC: 3200 AN: 10556

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.269 AC: 18245 AN: 67940

Other (OTH) AF: 0.233 AC: 491 AN: 2110

Alfa AF: 0.235 Hom.: 646

Bravo AF: 0.199

Asia WGS AF: 0.195 AC: 679 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.8
DANN	Benign	0.29
PhyloP100		-0.30
PromoterAI		0.012	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs4251969; hg19: chr2-113875753; COSMIC: COSV52079936; COSMIC: COSV52079936;