Genetic Variant IL1RN:n.-471-4683A>C (chr2-113106433-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000409052.6(IL1RN):n.-471-4683A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 152,146 control chromosomes in the GnomAD database, including 8,356 homozygotes. 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: 𝑓 0.32 ( 8356 hom., cov: 33)

Consequence

IL1RN
ENST00000409052.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.343

Publications

6 publications found

Variant links:

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

IL1RN links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
IL1RN	XM_011511121.2 link	c.-471-4683A>C	intron_variant	Intron 1 of 8	XP_011509423.1	P18510-4A0A024R528
IL1RN	XM_047444184.1 link	c.-643-781A>C	intron_variant	Intron 1 of 9	XP_047300140.1
IL1RN	XM_047444185.1 link	c.-600-4683A>C	intron_variant	Intron 1 of 9	XP_047300141.1
IL1RN	XM_047444186.1 link	c.-408-4683A>C	intron_variant	Intron 1 of 7	XP_047300142.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
IL1RN	ENST00000409052.6 link	n.-471-4683A>C	intron_variant	Intron 1 of 9	5	ENSP00000387210.1	P18510-4
IL1RN	ENST00000463073.6 link	n.104-4683A>C	intron_variant	Intron 1 of 3	5
IL1RN	ENST00000465812.6 link	n.276-781A>C	intron_variant	Intron 1 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.319

AC:

48467

AN:

152028

Hom.:

8350

Cov.:

show subpopulations

Gnomad AFR

AF:

0.232

Gnomad AMI

AF:

0.531

Gnomad AMR

AF:

0.321

Gnomad ASJ

AF:

0.389

Gnomad EAS

AF:

0.0673

Gnomad SAS

AF:

0.346

Gnomad FIN

AF:

0.299

Gnomad MID

AF:

0.449

Gnomad NFE

AF:

0.383

Gnomad OTH

AF:

0.352

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.319

AC:

48491

AN:

152146

Hom.:

8356

Cov.:

AF XY:

0.314

AC XY:

23310

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.232

AC:

9629

AN:

41510

American (AMR)

AF:

0.321

AC:

4900

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.389

AC:

1350

AN:

3470

East Asian (EAS)

AF:

0.0672

AC:

349

AN:

5192

South Asian (SAS)

AF:

0.347

AC:

1669

AN:

4804

European-Finnish (FIN)

AF:

0.299

AC:

3163

AN:

10580

Middle Eastern (MID)

AF:

0.452

AC:

133

AN:

294

European-Non Finnish (NFE)

AF:

0.383

AC:

26067

AN:

67990

Other (OTH)

AF:

0.355

AC:

747

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1696

3392

5087

6783

8479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

486

972

1458

1944

2430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.334

Hom.:

1113

Bravo

AF:

0.318

Asia WGS

AF:

0.257

AC:

892

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.61

(source)

DANN

Benign

0.67

PhyloP100

-0.34

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over