rs2228150

Variant names:

• chr10-6026006-C-T
• rs2228150
• NM_000417.3:c.84G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000417.3(IL2RA):​c.84G>A​(p.Pro28Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0382 in 1,613,062 control chromosomes in the GnomAD database, including 2,597 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (954 hom., cov: 33)
  • Exomes 𝑓: 0.034 (1643 hom.)
• Consequence: IL2RA NM_000417.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.67
• Publications: 21 publications found

Genes affected

IL2RA (HGNC:6008): (interleukin 2 receptor subunit alpha) The interleukin 2 (IL2) receptor alpha (IL2RA) and beta (IL2RB) chains, together with the common gamma chain (IL2RG), constitute the high-affinity IL2 receptor. Homodimeric alpha chains (IL2RA) result in low-affinity receptor, while homodimeric beta (IL2RB) chains produce a medium-affinity receptor. Normally an integral-membrane protein, soluble IL2RA has been isolated and determined to result from extracellular proteolyisis. Alternately-spliced IL2RA mRNAs have been isolated, but the significance of each is presently unknown. Mutations in this gene are associated with interleukin 2 receptor alpha deficiency. Patients with severe Coronavirus Disease 2019 (COVID-19), the disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have significantly elevated levels of IL2R in their plasma. Similarly, serum IL-2R levels are found to be elevated in patients with different types of carcinomas. Certain IL2RA and IL2RB gene polymorphisms have been associated with lung cancer risk. [provided by RefSeq, Jul 2020]

IL2RA Gene-Disease associations (from GenCC):

• immunodeficiency due to CD25 deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• neonatal diabetes mellitus

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• neonatal diabetes mellitus with congenital hypothyroidism

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• type 1 diabetes mellitus 10

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp

ENSG00000229664 (HGNC:58167):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-6026006-C-T is Benign according to our data. Variant chr10-6026006-C-T is described in ClinVar as Benign. ClinVar VariationId is 300261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RA	NM_000417.3	c.84G>A	p.Pro28Pro	synonymous_variant	Exon 2 of 8	ENST00000379959.8	NP_000408.1
IL2RA	NM_001308242.2	c.84G>A	p.Pro28Pro	synonymous_variant	Exon 2 of 7		NP_001295171.1
IL2RA	NM_001308243.2	c.84G>A	p.Pro28Pro	synonymous_variant	Exon 2 of 6		NP_001295172.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL2RA	ENST00000379959.8	c.84G>A	p.Pro28Pro	synonymous_variant	Exon 2 of 8	1	NM_000417.3	ENSP00000369293.3

Frequencies

GnomAD3 genomes AF: 0.0785 AC: 11935 AN: 152040 Hom.: 954 Cov.: 33

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.0868

Gnomad AMR AF: 0.0511

Gnomad ASJ AF: 0.0302

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.0605

Gnomad FIN AF: 0.0111

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0292

Gnomad OTH AF: 0.0718

GnomAD2 exomes AF: 0.0423 AC: 10638 AN: 251410 AF XY: 0.0415

Gnomad AFR exome AF: 0.205

Gnomad AMR exome AF: 0.0286

Gnomad ASJ exome AF: 0.0338

Gnomad EAS exome AF: 0.00147

Gnomad FIN exome AF: 0.0142

Gnomad NFE exome AF: 0.0299

Gnomad OTH exome AF: 0.0397

GnomAD4 exome AF: 0.0340 AC: 49701 AN: 1460902 Hom.: 1643 Cov.: 32 AF XY: 0.0348 AC XY: 25270 AN XY: 726748

African (AFR) AF: 0.210 AC: 7016 AN: 33442

American (AMR) AF: 0.0297 AC: 1329 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0337 AC: 881 AN: 26136

East Asian (EAS) AF: 0.000857 AC: 34 AN: 39696

South Asian (SAS) AF: 0.0676 AC: 5826 AN: 86204

European-Finnish (FIN) AF: 0.0147 AC: 785 AN: 53414

Middle Eastern (MID) AF: 0.0541 AC: 272 AN: 5028

European-Non Finnish (NFE) AF: 0.0279 AC: 31064 AN: 1111956

Other (OTH) AF: 0.0414 AC: 2494 AN: 60302

GnomAD4 genome AF: 0.0785 AC: 11938 AN: 152160 Hom.: 954 Cov.: 33 AF XY: 0.0771 AC XY: 5735 AN XY: 74390

African (AFR) AF: 0.203 AC: 8404 AN: 41476

American (AMR) AF: 0.0508 AC: 776 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0302 AC: 105 AN: 3472

East Asian (EAS) AF: 0.00250 AC: 13 AN: 5190

South Asian (SAS) AF: 0.0602 AC: 290 AN: 4820

European-Finnish (FIN) AF: 0.0111 AC: 118 AN: 10604

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0292 AC: 1987 AN: 68004

Other (OTH) AF: 0.0710 AC: 150 AN: 2112

Alfa AF: 0.0591 Hom.: 319

Bravo AF: 0.0859

Asia WGS AF: 0.0270 AC: 93 AN: 3478

EpiCase AF: 0.0304

EpiControl AF: 0.0327

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency due to CD25 deficiency Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.41
DANN	Benign	0.71
PhyloP100		-2.7
PromoterAI		-0.0093	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs2228150; hg19: chr10-6067969;