rs2228149

Variant names:

• chr10-6021545-G-A
• rs2228149
• NM_000417.3:c.516C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-6021545-G-A
• chr10-6021545-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000417.3(IL2RA):​c.516C>T​(p.His172His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0444 in 1,613,992 control chromosomes in the GnomAD database, including 2,904 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (354 hom., cov: 31)
  • Exomes 𝑓: 0.043 (2550 hom.)
• Consequence: IL2RA NM_000417.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.651
• 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: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• 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

LOC124902368 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 10-6021545-G-A is Benign according to our data. Variant chr10-6021545-G-A is described in ClinVar as Benign. ClinVar VariationId is 300256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.651 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000417.3. 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
	IL2RA	NM_000417.3	MANE Select	c.516C>T	p.His172His	synonymous	Exon 4 of 8	NP_000408.1	P01589
	IL2RA	NM_001308242.2		c.368-1604C>T		intron	N/A	NP_001295171.1	Q5W005
	IL2RA	NM_001308243.2		c.368-2046C>T		intron	N/A	NP_001295172.1	H0Y5Z0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RA	ENST00000379959.8	TSL:1 MANE Select	c.516C>T	p.His172His	synonymous	Exon 4 of 8	ENSP00000369293.3	P01589
	IL2RA	ENST00000379954.5	TSL:1	c.368-1604C>T		intron	N/A	ENSP00000369287.1	Q5W005
	IL2RA	ENST00000447847.2	TSL:1	c.368-2046C>T		intron	N/A	ENSP00000402024.2	H0Y5Z0

Frequencies

GnomAD3 genomes AF: 0.0548 AC: 8324 AN: 152030 Hom.: 348 Cov.: 31

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.0351

Gnomad EAS AF: 0.0507

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.0795

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0366

Gnomad OTH AF: 0.0617

GnomAD2 exomes AF: 0.0697 AC: 17528 AN: 251486 AF XY: 0.0615

Gnomad AFR exome AF: 0.0488

Gnomad AMR exome AF: 0.248

Gnomad ASJ exome AF: 0.0353

Gnomad EAS exome AF: 0.0507

Gnomad FIN exome AF: 0.0792

Gnomad NFE exome AF: 0.0370

Gnomad OTH exome AF: 0.0671

GnomAD4 exome AF: 0.0434 AC: 63379 AN: 1461844 Hom.: 2550 Cov.: 35 AF XY: 0.0420 AC XY: 30550 AN XY: 727224

African (AFR) AF: 0.0483 AC: 1618 AN: 33480

American (AMR) AF: 0.237 AC: 10612 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0358 AC: 936 AN: 26134

East Asian (EAS) AF: 0.0647 AC: 2567 AN: 39694

South Asian (SAS) AF: 0.0172 AC: 1480 AN: 86258

European-Finnish (FIN) AF: 0.0743 AC: 3967 AN: 53418

Middle Eastern (MID) AF: 0.0688 AC: 397 AN: 5768

European-Non Finnish (NFE) AF: 0.0351 AC: 39058 AN: 1111974

Other (OTH) AF: 0.0454 AC: 2744 AN: 60394

GnomAD4 genome AF: 0.0548 AC: 8334 AN: 152148 Hom.: 354 Cov.: 31 AF XY: 0.0575 AC XY: 4274 AN XY: 74388

African (AFR) AF: 0.0498 AC: 2068 AN: 41512

American (AMR) AF: 0.150 AC: 2299 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 122 AN: 3472

East Asian (EAS) AF: 0.0510 AC: 264 AN: 5172

South Asian (SAS) AF: 0.0168 AC: 81 AN: 4812

European-Finnish (FIN) AF: 0.0795 AC: 841 AN: 10580

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0366 AC: 2491 AN: 68000

Other (OTH) AF: 0.0605 AC: 128 AN: 2114

Alfa AF: 0.0451 Hom.: 585

Bravo AF: 0.0658

Asia WGS AF: 0.0340 AC: 118 AN: 3478

EpiCase AF: 0.0399

EpiControl AF: 0.0425

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Immunodeficiency due to CD25 deficiency (2)
-	-	1	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.49
DANN	Benign	0.57
PhyloP100		-0.65
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: rs2228149; hg19: chr10-6063508;