2-113131216-A-T

Variant names:

• chr2-113131216-A-T
• rs454078
• NM_173842.3:c.318+59A>T

Variant summary

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

The NM_173842.3(IL1RN):​c.318+59A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,034,722 control chromosomes in the GnomAD database, including 35,094 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4274 hom., cov: 30)
  • Exomes 𝑓: 0.25 (30820 hom.)
• Consequence: IL1RN NM_173842.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.532
• Publications: 31 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-113131216-A-T is Benign according to our data. Variant chr2-113131216-A-T is described in ClinVar as Benign. ClinVar VariationId is 1260921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL1RN	NM_173842.3	c.318+59A>T		intron_variant	Intron 3 of 3	ENST00000409930.4	NP_776214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL1RN	ENST00000409930.4	c.318+59A>T		intron_variant	Intron 3 of 3	1	NM_173842.3	ENSP00000387173.3

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32743 AN: 151872 Hom.: 4264 Cov.: 30

Gnomad AFR AF: 0.0694

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.0780

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.238

GnomAD4 exome AF: 0.253 AC: 223473 AN: 882732 Hom.: 30820 AF XY: 0.254 AC XY: 117533 AN XY: 462502

African (AFR) AF: 0.0628 AC: 1440 AN: 22924

American (AMR) AF: 0.322 AC: 13956 AN: 43370

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 6490 AN: 22482

East Asian (EAS) AF: 0.0585 AC: 2174 AN: 37160

South Asian (SAS) AF: 0.276 AC: 20501 AN: 74396

European-Finnish (FIN) AF: 0.298 AC: 15773 AN: 52932

Middle Eastern (MID) AF: 0.213 AC: 999 AN: 4686

European-Non Finnish (NFE) AF: 0.260 AC: 151896 AN: 583276

Other (OTH) AF: 0.247 AC: 10244 AN: 41506

GnomAD4 genome AF: 0.216 AC: 32782 AN: 151990 Hom.: 4274 Cov.: 30 AF XY: 0.219 AC XY: 16254 AN XY: 74290

African (AFR) AF: 0.0698 AC: 2895 AN: 41450

American (AMR) AF: 0.286 AC: 4376 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1010 AN: 3470

East Asian (EAS) AF: 0.0774 AC: 400 AN: 5168

South Asian (SAS) AF: 0.286 AC: 1377 AN: 4808

European-Finnish (FIN) AF: 0.305 AC: 3219 AN: 10548

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.275 AC: 18711 AN: 67948

Other (OTH) AF: 0.240 AC: 506 AN: 2112

Alfa AF: 0.240 Hom.: 674

Bravo AF: 0.206

Asia WGS AF: 0.197 AC: 687 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 46% of patients studied by a panel of primary immunodeficiencies. Number of patients: 44. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.092
DANN	Benign	0.69
PhyloP100		-0.53
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: rs454078; hg19: chr2-113888793; COSMIC: COSV52080160; COSMIC: COSV52080160;