2-113129630-T-C

Variant names:

• chr2-113129630-T-C
• rs419598
• NM_173842.3:c.171T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_173841.3(IL1RN):​c.180T>C​(p.Ala60Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 1,609,674 control chromosomes in the GnomAD database, including 59,383 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4288 hom., cov: 32)
  • Exomes 𝑓: 0.27 (55095 hom.)
• Consequence: IL1RN NM_173841.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.00
• Publications: 168 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 2-113129630-T-C is Benign according to our data. Variant chr2-113129630-T-C is described in ClinVar as Benign. ClinVar VariationId is 330825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.276 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL1RN	NM_173842.3	MANE Select	c.171T>C	p.Ala57Ala	synonymous	Exon 2 of 4	NP_776214.1
	IL1RN	NM_173841.3		c.180T>C	p.Ala60Ala	synonymous	Exon 4 of 6	NP_776213.1
	IL1RN	NM_000577.5		c.117T>C	p.Ala39Ala	synonymous	Exon 3 of 5	NP_000568.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL1RN	ENST00000409930.4	TSL:1 MANE Select	c.171T>C	p.Ala57Ala	synonymous	Exon 2 of 4	ENSP00000387173.3
	IL1RN	ENST00000259206.9	TSL:1	c.180T>C	p.Ala60Ala	synonymous	Exon 4 of 6	ENSP00000259206.5
	IL1RN	ENST00000354115.6	TSL:1	c.117T>C	p.Ala39Ala	synonymous	Exon 3 of 5	ENSP00000329072.3

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32829 AN: 152038 Hom.: 4280 Cov.: 32

Gnomad AFR AF: 0.0704

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.0777

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.239

GnomAD2 exomes AF: 0.256 AC: 64470 AN: 251432 AF XY: 0.259

Gnomad AFR exome AF: 0.0651

Gnomad AMR exome AF: 0.321

Gnomad ASJ exome AF: 0.297

Gnomad EAS exome AF: 0.0708

Gnomad FIN exome AF: 0.305

Gnomad NFE exome AF: 0.273

Gnomad OTH exome AF: 0.266

GnomAD4 exome AF: 0.268 AC: 390790 AN: 1457516 Hom.: 55095 Cov.: 30 AF XY: 0.268 AC XY: 194275 AN XY: 725298

African (AFR) AF: 0.0625 AC: 2090 AN: 33454

American (AMR) AF: 0.317 AC: 14180 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 7547 AN: 26098

East Asian (EAS) AF: 0.0600 AC: 2380 AN: 39694

South Asian (SAS) AF: 0.281 AC: 24223 AN: 86150

European-Finnish (FIN) AF: 0.300 AC: 16009 AN: 53408

Middle Eastern (MID) AF: 0.219 AC: 1259 AN: 5762

European-Non Finnish (NFE) AF: 0.278 AC: 307678 AN: 1107982

Other (OTH) AF: 0.256 AC: 15424 AN: 60250

GnomAD4 genome AF: 0.216 AC: 32867 AN: 152158 Hom.: 4288 Cov.: 32 AF XY: 0.219 AC XY: 16273 AN XY: 74386

African (AFR) AF: 0.0708 AC: 2941 AN: 41528

American (AMR) AF: 0.283 AC: 4329 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1010 AN: 3472

East Asian (EAS) AF: 0.0771 AC: 400 AN: 5188

South Asian (SAS) AF: 0.289 AC: 1392 AN: 4820

European-Finnish (FIN) AF: 0.305 AC: 3228 AN: 10572

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

European-Non Finnish (NFE) AF: 0.276 AC: 18772 AN: 67978

Other (OTH) AF: 0.240 AC: 506 AN: 2108

Alfa AF: 0.257 Hom.: 11414

Bravo AF: 0.206

Asia WGS AF: 0.196 AC: 683 AN: 3478

EpiCase AF: 0.272

EpiControl AF: 0.268

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	Sterile multifocal osteomyelitis with periostitis and pustulosis (2)
-	-	1	Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	2.3
DANN	Benign	0.52
PhyloP100		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs419598; hg19: chr2-113887207; COSMIC: COSV52080055;