22-37148496-G-T

Variant names:

• chr22-37148496-G-T
• rs3218254
• NM_000878.5:c.-34+1329C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000878.5(IL2RB):​c.-34+1329C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00502 in 152,244 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0050 (3 hom., cov: 32)
• Consequence: IL2RB NM_000878.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00300
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00502 (765/152244) while in subpopulation AMR AF = 0.00869 (133/15300). AF 95% confidence interval is 0.00749. There are 3 homozygotes in GnomAd4. There are 358 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.-34+1329C>A		intron	N/A	NP_000869.1	P14784
	IL2RB	NM_001346222.1		c.-33-4291C>A		intron	N/A	NP_001333151.1	P14784
	IL2RB	NM_001346223.2		c.-33-4291C>A		intron	N/A	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.-34+1329C>A		intron	N/A	ENSP00000216223.5	P14784
	IL2RB	ENST00000698894.2		c.-34+1329C>A		intron	N/A	ENSP00000514013.1	A0A8V8TMD3
	IL2RB	ENST00000429622.6	TSL:4	c.-33-4291C>A		intron	N/A	ENSP00000402685.2	P14784

Frequencies

GnomAD3 genomes AF: 0.00503 AC: 765 AN: 152126 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.00870

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00584

Gnomad OTH AF: 0.00958

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00502 AC: 765 AN: 152244 Hom.: 3 Cov.: 32 AF XY: 0.00481 AC XY: 358 AN XY: 74442

African (AFR) AF: 0.00130 AC: 54 AN: 41528

American (AMR) AF: 0.00869 AC: 133 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4828

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10606

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00584 AC: 397 AN: 68012

Other (OTH) AF: 0.00948 AC: 20 AN: 2110

Alfa AF: 0.00531 Hom.: 2

Bravo AF: 0.00596

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.1
DANN	Benign	0.56
PhyloP100		0.0030

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: rs3218254; hg19: chr22-37544536;