22-37128113-G-A

Position:

• chr22-37128113-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000216223.10(IL2RB):​c.1639C>T​(p.Pro547Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IL2RB ENST00000216223.10 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.23

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11035389).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL2RB	NM_000878.5	c.1639C>T	p.Pro547Ser	missense_variant	10/10	ENST00000216223.10	NP_000869.1
IL2RB	NM_001346222.1	c.1639C>T	p.Pro547Ser	missense_variant	10/10		NP_001333151.1
IL2RB	NM_001346223.2	c.1639C>T	p.Pro547Ser	missense_variant	10/10		NP_001333152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL2RB	ENST00000216223.10	c.1639C>T	p.Pro547Ser	missense_variant	10/10	1	NM_000878.5	ENSP00000216223	P4

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1416942 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 703552

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74404

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2024

The c.1639C>T (p.P547S) alteration is located in exon 10 (coding exon 9) of the IL2RB gene. This alteration results from a C to T substitution at nucleotide position 1639, causing the proline (P) at amino acid position 547 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 05, 2022

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 547 of the IL2RB protein (p.Pro547Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IL2RB-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Benign	0.026
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.080
Sift	Benign	0.24	T
Sift4G	Benign	0.34	T
Polyphen		0.90	P
Vest4		0.25
MutPred		0.19		Gain of disorder (P = 0.151);
MVP		0.33
MPC		0.34
ClinPred		0.46	T
GERP RS		3.6
Varity_R		0.040
gMVP		0.13

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

LitVar

Other links and lift over

dbSNP: rs573251262; hg19: chr22-37524153;