rs72650666

Variant names:

• chr10-6024339-G-A
• rs72650666
• NM_000417.3:c.272C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-6024339-G-A
• chr10-6024339-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000417.3(IL2RA):​c.272C>T​(p.Thr91Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,612,798 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T91T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (2 hom.)
• Consequence: IL2RA NM_000417.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -1.06
• Publications: 10 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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051365495).
• BP6: Variant 10-6024339-G-A is Benign according to our data. Variant chr10-6024339-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 432884.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00171 (261/152266) while in subpopulation NFE AF = 0.00178 (121/68004). AF 95% confidence interval is 0.00152. There are 0 homozygotes in GnomAd4. There are 150 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.272C>T	p.Thr91Met	missense	Exon 3 of 8	NP_000408.1	P01589
	IL2RA	NM_001308242.2		c.272C>T	p.Thr91Met	missense	Exon 3 of 7	NP_001295171.1	Q5W005
	IL2RA	NM_001308243.2		c.272C>T	p.Thr91Met	missense	Exon 3 of 6	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.272C>T	p.Thr91Met	missense	Exon 3 of 8	ENSP00000369293.3	P01589
	IL2RA	ENST00000379954.5	TSL:1	c.272C>T	p.Thr91Met	missense	Exon 3 of 7	ENSP00000369287.1	Q5W005
	IL2RA	ENST00000447847.2	TSL:1	c.272C>T	p.Thr91Met	missense	Exon 3 of 6	ENSP00000402024.2	H0Y5Z0

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 261 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00178

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00186 AC: 468 AN: 251436 AF XY: 0.00188

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00975

Gnomad NFE exome AF: 0.00200

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00186 AC: 2713 AN: 1460532 Hom.: 2 Cov.: 31 AF XY: 0.00185 AC XY: 1343 AN XY: 726664

African (AFR) AF: 0.000209 AC: 7 AN: 33446

American (AMR) AF: 0.000335 AC: 15 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86226

European-Finnish (FIN) AF: 0.0101 AC: 540 AN: 53418

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00187 AC: 2074 AN: 1110760

Other (OTH) AF: 0.00118 AC: 71 AN: 60368

GnomAD4 genome AF: 0.00171 AC: 261 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.00201 AC XY: 150 AN XY: 74448

African (AFR) AF: 0.000361 AC: 15 AN: 41558

American (AMR) AF: 0.000981 AC: 15 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0101 AC: 107 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00178 AC: 121 AN: 68004

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00143 Hom.: 0

Bravo AF: 0.000808

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00173 AC: 210

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Immunodeficiency due to CD25 deficiency (2)
-	1	1	not provided (2)
-	-	1	IL2RA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.2
DANN	Benign	0.77
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N
PhyloP100		-1.1
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.069
Sift	Benign	0.098	T
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.15
MVP		0.47
MPC		0.39
ClinPred		0.011	T
GERP RS		-5.5
Varity_R		0.016
gMVP		0.25
Mutation Taster		=95/5	polymorphism

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: rs72650666; hg19: chr10-6066302;