Genetic Variant IL2RB:c.-33-14594G>C (chr22-37158799-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001346222.1(IL2RB):c.-33-14594G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 152,124 control chromosomes in the GnomAD database, including 13,568 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 0.41 ( 13568 hom., cov: 32)

Consequence

IL2RB
NM_001346222.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.97

Publications

8 publications found

Variant links:

Genes affected

IL2RB (HGNC:6009): (interleukin 2 receptor subunit beta) The interleukin 2 receptor, which is involved in T cell-mediated immune responses, is present in 3 forms with respect to ability to bind interleukin 2. The low affinity form is a monomer of the alpha subunit and is not involved in signal transduction. The intermediate affinity form consists of an alpha/beta subunit heterodimer, while the high affinity form consists of an alpha/beta/gamma subunit heterotrimer. Both the intermediate and high affinity forms of the receptor are involved in receptor-mediated endocytosis and transduction of mitogenic signals from interleukin 2. The protein encoded by this gene represents the beta subunit and is a type I membrane protein. The use of alternative promoters results in multiple transcript variants encoding the same protein. The protein is primarily expressed in the hematopoietic system. The use by some variants of an alternate promoter in an upstream long terminal repeat (LTR) results in placenta-specific expression. [provided by RefSeq, Sep 2016]

IL2RB Gene-Disease associations (from GenCC):

immunodeficiency 63 with lymphoproliferation and autoimmunity
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

IL2RB 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 (AFR) allele frequency at 95% confidence interval = 0.54 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RB	NM_001346222.1 link	c.-33-14594G>C		intron_variant	Intron 1 of 9		NP_001333151.1	P14784
IL2RB	NM_001346223.2 link	c.-33-14594G>C		intron_variant	Intron 1 of 9		NP_001333152.1	P14784

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
IL2RB	ENST00000429622.6 link	c.-33-14594G>C	intron_variant	Intron 1 of 9	4	ENSP00000402685.2	P14784B0QYC1
IL2RB	ENST00000445595.2 link	c.-34+2994G>C	intron_variant	Intron 2 of 10	4	ENSP00000401020.2	P14784B0QYC2
IL2RB	ENST00000453962.6 link	c.-33-14594G>C	intron_variant	Intron 1 of 9	4	ENSP00000403731.2	P14784B0QYC0

Frequencies

GnomAD3 genomes

AF:

0.413

AC:

62849

AN:

152006

Hom.:

13536

Cov.:

show subpopulations

Gnomad AFR

AF:

0.546

Gnomad AMI

AF:

0.395

Gnomad AMR

AF:

0.350

Gnomad ASJ

AF:

0.319

Gnomad EAS

AF:

0.342

Gnomad SAS

AF:

0.279

Gnomad FIN

AF:

0.386

Gnomad MID

AF:

0.320

Gnomad NFE

AF:

0.373

Gnomad OTH

AF:

0.383

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

GnomAD4 genome

AF:

0.414

AC:

62928

AN:

152124

Hom.:

13568

Cov.:

AF XY:

0.410

AC XY:

30499

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.546

AC:

22680

AN:

41520

American (AMR)

AF:

0.350

AC:

5347

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.319

AC:

1106

AN:

3464

East Asian (EAS)

AF:

0.342

AC:

1769

AN:

5176

South Asian (SAS)

AF:

0.278

AC:

1342

AN:

4822

European-Finnish (FIN)

AF:

0.386

AC:

4074

AN:

10568

Middle Eastern (MID)

AF:

0.323

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.373

AC:

25356

AN:

67976

Other (OTH)

AF:

0.378

AC:

800

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1863

3727

5590

7454

9317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

574

1148

1722

2296

2870

<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:

0.222

Hom.:

425

Bravo

AF:

0.421

Asia WGS

AF:

0.337

AC:

1176

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.85

(source)

DANN

Benign

0.45

PhyloP100

-3.0

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