22-37128164-G-A

Variant names:

• chr22-37128164-G-A
• rs1921216111
• NM_000878.5:c.1588C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000878.5(IL2RB):​c.1588C>T​(p.Pro530Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000424 in 1,415,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: IL2RB NM_000878.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.734
• Publications: 0 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, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058991402).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RB	NM_000878.5	MANE Select	c.1588C>T	p.Pro530Ser	missense	Exon 10 of 10	NP_000869.1	P14784
	IL2RB	NM_001346222.1		c.1588C>T	p.Pro530Ser	missense	Exon 10 of 10	NP_001333151.1	P14784
	IL2RB	NM_001346223.2		c.1588C>T	p.Pro530Ser	missense	Exon 10 of 10	NP_001333152.1	P14784

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RB	ENST00000216223.10	TSL:1 MANE Select	c.1588C>T	p.Pro530Ser	missense	Exon 10 of 10	ENSP00000216223.5	P14784
	IL2RB	ENST00000698894.2		c.1606C>T	p.Pro536Ser	missense	Exon 10 of 10	ENSP00000514013.1	A0A8V8TMD3
	IL2RB	ENST00000429622.6	TSL:4	c.1588C>T	p.Pro530Ser	missense	Exon 10 of 10	ENSP00000402685.2	P14784

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000424 AC: 6 AN: 1415320 Hom.: 0 Cov.: 32 AF XY: 0.00000285 AC XY: 2 AN XY: 701884

African (AFR) AF: 0.00 AC: 0 AN: 31374

American (AMR) AF: 0.00 AC: 0 AN: 35404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22988

East Asian (EAS) AF: 0.00 AC: 0 AN: 38034

South Asian (SAS) AF: 0.00 AC: 0 AN: 77964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51968

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5568

European-Non Finnish (NFE) AF: 0.00000549 AC: 6 AN: 1093746

Other (OTH) AF: 0.00 AC: 0 AN: 58274

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.0050
DANN	Benign	0.39
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.41	N
PhyloP100		-0.73
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.018
Sift	Benign	0.75	T
Sift4G	Benign	0.24	T
Polyphen		0.023	B
Vest4		0.026
MutPred		0.36		Gain of sheet (P = 0.0149)
MVP		0.14
MPC		0.092
ClinPred		0.030	T
GERP RS		-8.1
Varity_R		0.021
gMVP		0.052
Mutation Taster		=96/4	polymorphism

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: rs1921216111; hg19: chr22-37524204;