22-37128169-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_000878.5(IL2RB):c.1583G>A(p.Arg528His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000467 in 1,564,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R528C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

IL2RB
NM_000878.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.153

Publications

0 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, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

IL2RB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13411918).

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000482 (68/1412142) while in subpopulation SAS AF = 0.000297 (23/77374). AF 95% confidence interval is 0.000202. There are 0 homozygotes in GnomAdExome4. There are 43 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000878.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL2RB	NM_000878.5	MANE Select	c.1583G>A	p.Arg528His	missense	Exon 10 of 10	NP_000869.1	P14784
IL2RB	NM_001346222.1		c.1583G>A	p.Arg528His	missense	Exon 10 of 10	NP_001333151.1	P14784
IL2RB	NM_001346223.2		c.1583G>A	p.Arg528His	missense	Exon 10 of 10	NP_001333152.1	P14784

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL2RB	ENST00000216223.10	TSL:1 MANE Select	c.1583G>A	p.Arg528His	missense	Exon 10 of 10	ENSP00000216223.5	P14784
IL2RB	ENST00000698894.2		c.1601G>A	p.Arg534His	missense	Exon 10 of 10	ENSP00000514013.1	A0A8V8TMD3
IL2RB	ENST00000429622.6	TSL:4	c.1583G>A	p.Arg528His	missense	Exon 10 of 10	ENSP00000402685.2	P14784

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000652

AC:

AN:

199516

AF XY:

0.0000652

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000482

AC:

AN:

1412142

Hom.:

Cov.:

AF XY:

0.0000614

AC XY:

AN XY:

700102

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31264

American (AMR)

AF:

0.00

AC:

AN:

35022

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22786

East Asian (EAS)

AF:

0.00

AC:

AN:

37992

South Asian (SAS)

AF:

0.000297

AC:

AN:

77374

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51874

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5552

European-Non Finnish (NFE)

AF:

0.0000375

AC:

AN:

1092180

Other (OTH)

AF:

0.0000688

AC:

AN:

58098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152036

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41398

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000102

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000660

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.31

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.47

M_CAP

Benign

0.015

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

-0.15

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.57

REVEL

Benign

0.092

Sift

Benign

0.25

Sift4G

Benign

0.28

Polyphen

0.99

Vest4

0.014

MutPred

0.33

Loss of stability (P = 0.0603)

MVP

0.35

MPC

0.11

ClinPred

0.044

GERP RS

-1.5

Varity_R

0.020

gMVP

0.084

Mutation Taster

=98/2

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over