chr22-37135396-G-A

Variant names:

• chr22-37135396-G-A
• rs228953
• NM_000878.5:c.750C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000878.5(IL2RB):​c.750C>T​(p.Gly250Gly) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G250G) has been classified as Likely 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:5
• Conservation: PhyloP100: 0.458
• Publications: 43 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.045).
• BP6: Variant 22-37135396-G-A is Benign according to our data. Variant chr22-37135396-G-A is described in ClinVar as Benign. ClinVar VariationId 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.

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.750C>T	p.Gly250Gly	synonymous	Exon 8 of 10	NP_000869.1	P14784
	IL2RB	NM_001346222.1		c.750C>T	p.Gly250Gly	synonymous	Exon 8 of 10	NP_001333151.1	P14784
	IL2RB	NM_001346223.2		c.750C>T	p.Gly250Gly	synonymous	Exon 8 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.750C>T	p.Gly250Gly	synonymous	Exon 8 of 10	ENSP00000216223.5	P14784
	IL2RB	ENST00000698894.2		c.768C>T	p.Gly256Gly	synonymous	Exon 8 of 10	ENSP00000514013.1	A0A8V8TMD3
	IL2RB	ENST00000429622.6	TSL:4	c.750C>T	p.Gly250Gly	synonymous	Exon 8 of 10	ENSP00000402685.2	P14784

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

GnomAD2 exomes AF: 0.423 AC: 106366 AN: 251204 AF XY: 0.422

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 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

African (AFR) AF: 0.405 AC: 13559 AN: 33464

American (AMR) AF: 0.403 AC: 18033 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 9896 AN: 26106

East Asian (EAS) AF: 0.440 AC: 17465 AN: 39668

South Asian (SAS) AF: 0.372 AC: 32065 AN: 86216

European-Finnish (FIN) AF: 0.517 AC: 27608 AN: 53386

Middle Eastern (MID) AF: 0.304 AC: 1751 AN: 5762

European-Non Finnish (NFE) AF: 0.437 AC: 485097 AN: 1110942

Other (OTH) AF: 0.414 AC: 25010 AN: 60352

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

African (AFR) AF: 0.412 AC: 17080 AN: 41422

American (AMR) AF: 0.420 AC: 6426 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 1346 AN: 3468

East Asian (EAS) AF: 0.420 AC: 2171 AN: 5164

South Asian (SAS) AF: 0.371 AC: 1787 AN: 4820

European-Finnish (FIN) AF: 0.534 AC: 5641 AN: 10562

Middle Eastern (MID) AF: 0.336 AC: 98 AN: 292

European-Non Finnish (NFE) AF: 0.434 AC: 29475 AN: 67918

Other (OTH) AF: 0.389 AC: 820 AN: 2108

Alfa AF: 0.423 Hom.: 25869

Bravo AF: 0.422

Asia WGS AF: 0.407 AC: 1414 AN: 3478

EpiCase AF: 0.417

EpiControl AF: 0.416

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	IL2RB-related disorder (1)
-	-	1	Immunodeficiency 63 with lymphoproliferation and autoimmunity (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.4
DANN	Benign	0.64
PhyloP100		0.46
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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