22-37128579-G-T

Variant names:

• chr22-37128579-G-T
• rs228942
• NM_000878.5:c.1173C>A

Variant summary

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

The NM_000878.5(IL2RB):​c.1173C>A​(p.Asp391Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 1,613,818 control chromosomes in the GnomAD database, including 26,470 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2482 hom., cov: 32)
  • Exomes 𝑓: 0.18 (23988 hom.)
• Consequence: IL2RB NM_000878.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.49
• Publications: 45 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039142966).
• BP6: Variant 22-37128579-G-T is Benign according to our data. Variant chr22-37128579-G-T is described in ClinVar as Benign. ClinVar VariationId is 1164671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RB	NM_000878.5	c.1173C>A	p.Asp391Glu	missense_variant	Exon 10 of 10	ENST00000216223.10	NP_000869.1
IL2RB	NM_001346222.1	c.1173C>A	p.Asp391Glu	missense_variant	Exon 10 of 10		NP_001333151.1
IL2RB	NM_001346223.2	c.1173C>A	p.Asp391Glu	missense_variant	Exon 10 of 10		NP_001333152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL2RB	ENST00000216223.10	c.1173C>A	p.Asp391Glu	missense_variant	Exon 10 of 10	1	NM_000878.5	ENSP00000216223.5

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25569 AN: 152022 Hom.: 2480 Cov.: 32

Gnomad AFR AF: 0.0954

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.160

GnomAD2 exomes AF: 0.192 AC: 48194 AN: 251134 AF XY: 0.187

Gnomad AFR exome AF: 0.0916

Gnomad AMR exome AF: 0.293

Gnomad ASJ exome AF: 0.194

Gnomad EAS exome AF: 0.265

Gnomad FIN exome AF: 0.186

Gnomad NFE exome AF: 0.176

Gnomad OTH exome AF: 0.176

GnomAD4 exome AF: 0.178 AC: 259785 AN: 1461678 Hom.: 23988 Cov.: 35 AF XY: 0.176 AC XY: 128079 AN XY: 727164

African (AFR) AF: 0.0906 AC: 3033 AN: 33480

American (AMR) AF: 0.288 AC: 12892 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 4990 AN: 26132

East Asian (EAS) AF: 0.259 AC: 10284 AN: 39698

South Asian (SAS) AF: 0.150 AC: 12957 AN: 86254

European-Finnish (FIN) AF: 0.187 AC: 9986 AN: 53412

Middle Eastern (MID) AF: 0.0935 AC: 539 AN: 5766

European-Non Finnish (NFE) AF: 0.175 AC: 194982 AN: 1111838

Other (OTH) AF: 0.168 AC: 10122 AN: 60386

GnomAD4 genome AF: 0.168 AC: 25568 AN: 152140 Hom.: 2482 Cov.: 32 AF XY: 0.171 AC XY: 12744 AN XY: 74360

African (AFR) AF: 0.0953 AC: 3957 AN: 41512

American (AMR) AF: 0.256 AC: 3917 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 700 AN: 3470

East Asian (EAS) AF: 0.252 AC: 1298 AN: 5148

South Asian (SAS) AF: 0.155 AC: 747 AN: 4826

European-Finnish (FIN) AF: 0.195 AC: 2067 AN: 10604

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.180 AC: 12241 AN: 67960

Other (OTH) AF: 0.158 AC: 333 AN: 2108

Alfa AF: 0.175 Hom.: 10682

Bravo AF: 0.171

TwinsUK AF: 0.180 AC: 667

ALSPAC AF: 0.186 AC: 715

ESP6500AA AF: 0.0921 AC: 406

ESP6500EA AF: 0.184 AC: 1585

ExAC AF: 0.185 AC: 22419

Asia WGS AF: 0.169 AC: 590 AN: 3478

EpiCase AF: 0.170

EpiControl AF: 0.170

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 24, 2024

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 47% of patients studied by a panel of primary immunodeficiencies. Number of patients: 41. Only high quality variants are reported. -

IL2RB-related disorder Benign:1

Nov 05, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.0080
DANN	Benign	0.20
DEOGEN2	Benign	0.29	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.1	N
PhyloP100		-2.5
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.071
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.011
MutPred		0.15		Gain of glycosylation at P386 (P = 0.1426);
MPC		0.079
ClinPred		0.00030	T
GERP RS		2.2
Varity_R		0.036
gMVP		0.054
Mutation Taster		=98/2	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: rs228942; hg19: chr22-37524619; COSMIC: COSV53426431;