rs228953

chr22-37135396-G-Achr22-37135396-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000878.5(IL2RB):c.750C>T(p.Gly250=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 1,612,546 control chromosomes in the GnomAD database, including 151,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14137 hom., cov: 32)
  • Exomes 𝑓: 0.43 (136966 hom.)
• Consequence: IL2RB NM_000878.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.458

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 22-37135396-G-A is Benign according to our data. Variant chr22-37135396-G-A is described in ClinVar as [Benign]. Clinvar id is 1170851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.458 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL2RB	NM_000878.5	c.750C>T	p.Gly250=	synonymous_variant	8/10	ENST00000216223.10
IL2RB	NM_001346222.1	c.750C>T	p.Gly250=	synonymous_variant	8/10
IL2RB	NM_001346223.2	c.750C>T	p.Gly250=	synonymous_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL2RB	ENST00000216223.10	c.750C>T	p.Gly250=	synonymous_variant	8/10	1	NM_000878.5	P4

Frequencies

GnomAD3 genomes AF: 0.430 AC: 65222 AN: 151830 Hom.: 14127 Cov.: 32

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.469

Gnomad AMR AF: 0.421

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.420

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.344

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.394

GnomAD3 exomes AF: 0.423 AC: 106366 AN: 251204 Hom.: 22781 AF XY: 0.422 AC XY: 57234 AN XY: 135784

Gnomad AFR exome AF: 0.409

Gnomad AMR exome AF: 0.402

Gnomad ASJ exome AF: 0.383

Gnomad EAS exome AF: 0.425

Gnomad SAS exome AF: 0.369

Gnomad FIN exome AF: 0.526

Gnomad NFE exome AF: 0.431

Gnomad OTH exome AF: 0.412

GnomAD4 exome AF: 0.432 AC: 630484 AN: 1460598 Hom.: 136966 Cov.: 38 AF XY: 0.429 AC XY: 311952 AN XY: 726732

Gnomad4 AFR exome AF: 0.405

Gnomad4 AMR exome AF: 0.403

Gnomad4 ASJ exome AF: 0.379

Gnomad4 EAS exome AF: 0.440

Gnomad4 SAS exome AF: 0.372

Gnomad4 FIN exome AF: 0.517

Gnomad4 NFE exome AF: 0.437

Gnomad4 OTH exome AF: 0.414

GnomAD4 genome AF: 0.430 AC: 65271 AN: 151948 Hom.: 14137 Cov.: 32 AF XY: 0.436 AC XY: 32390 AN XY: 74280

Gnomad4 AFR AF: 0.412

Gnomad4 AMR AF: 0.420

Gnomad4 ASJ AF: 0.388

Gnomad4 EAS AF: 0.420

Gnomad4 SAS AF: 0.371

Gnomad4 FIN AF: 0.534

Gnomad4 NFE AF: 0.434

Gnomad4 OTH AF: 0.389

Alfa AF: 0.422 Hom.: 17733

Bravo AF: 0.422

Asia WGS AF: 0.407 AC: 1414 AN: 3478

EpiCase AF: 0.417

EpiControl AF: 0.416

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 69% of patients studied by a panel of primary immunodeficiencies. Number of patients: 61. Only high quality variants are reported. -

IL2RB-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2019

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Immunodeficiency 63 with lymphoproliferation and autoimmunity Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	2.4
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs228953; hg19: chr22-37531436; COSMIC: COSV53425893; COSMIC: COSV53425893;