Genetic Variant IL1RN:c.116+451G>A (chr2-113128191-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_173842.3(IL1RN):c.116+451G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0629 in 152,308 control chromosomes in the GnomAD database, including 395 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 0.063 ( 395 hom., cov: 32)

Consequence

IL1RN
NM_173842.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.680

Publications

16 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=-0.9).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0958 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173842.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
IL1RN	NM_173842.3	MANE Select	c.116+451G>A	intron	N/A	NP_776214.1
IL1RN	NM_173841.3		c.125+451G>A	intron	N/A	NP_776213.1
IL1RN	NM_000577.5		c.62+451G>A	intron	N/A	NP_000568.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
IL1RN	ENST00000409930.4	TSL:1 MANE Select	c.116+451G>A	intron	N/A	ENSP00000387173.3
IL1RN	ENST00000259206.9	TSL:1	c.125+451G>A	intron	N/A	ENSP00000259206.5
IL1RN	ENST00000354115.6	TSL:1	c.62+451G>A	intron	N/A	ENSP00000329072.3

Frequencies

GnomAD3 genomes

AF:

0.0630

AC:

9582

AN:

152190

Hom.:

396

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0174

Gnomad AMI

AF:

0.0976

Gnomad AMR

AF:

0.0628

Gnomad ASJ

AF:

0.0539

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0147

Gnomad FIN

AF:

0.0702

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0978

Gnomad OTH

AF:

0.0669

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

GnomAD4 genome

AF:

0.0629

AC:

9576

AN:

152308

Hom.:

395

Cov.:

AF XY:

0.0602

AC XY:

4481

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0174

AC:

724

AN:

41562

American (AMR)

AF:

0.0626

AC:

958

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0539

AC:

187

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.0147

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0702

AC:

745

AN:

10618

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0977

AC:

6648

AN:

68022

Other (OTH)

AF:

0.0662

AC:

140

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

494

987

1481

1974

2468

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<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:

0.0551

Hom.:

Bravo

AF:

0.0606

Asia WGS

AF:

0.00953

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.93

(source)

DANN

Benign

0.74

PhyloP100

-0.68

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over