rs12722525

Variant names:

• chr10-6035857-G-A
• rs12722525
• NM_000417.3:c.65-9832C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-6035857-G-A
• chr10-6035857-G-C

Variant summary

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

The NM_000417.3(IL2RA):​c.65-9832C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0287 in 152,276 control chromosomes in the GnomAD database, including 94 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 0.029 (94 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IL2RA NM_000417.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.20
• Publications: 3 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

IL2RA-AS1 (HGNC:58167):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0287 (4363/152276) while in subpopulation AMR AF = 0.0467 (714/15294). AF 95% confidence interval is 0.0438. There are 94 homozygotes in GnomAd4. There are 2160 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 94 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RA	NM_000417.3	MANE Select	c.65-9832C>T		intron	N/A	NP_000408.1
	IL2RA	NM_001308242.2		c.65-9832C>T		intron	N/A	NP_001295171.1
	IL2RA	NM_001308243.2		c.65-9832C>T		intron	N/A	NP_001295172.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RA	ENST00000379959.8	TSL:1 MANE Select	c.65-9832C>T		intron	N/A	ENSP00000369293.3
	IL2RA	ENST00000379954.5	TSL:1	c.65-9832C>T		intron	N/A	ENSP00000369287.1
	IL2RA	ENST00000447847.2	TSL:1	c.65-9832C>T		intron	N/A	ENSP00000402024.2

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 4356 AN: 152158 Hom.: 94 Cov.: 33

Gnomad AFR AF: 0.0385

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0467

Gnomad ASJ AF: 0.0403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0364

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0426

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 58 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 52

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 34

Other (OTH) AF: 0.00 AC: 0 AN: 12

GnomAD4 genome AF: 0.0287 AC: 4363 AN: 152276 Hom.: 94 Cov.: 33 AF XY: 0.0290 AC XY: 2160 AN XY: 74476

African (AFR) AF: 0.0386 AC: 1603 AN: 41522

American (AMR) AF: 0.0467 AC: 714 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0403 AC: 140 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0360 AC: 174 AN: 4832

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10620

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0231 AC: 1574 AN: 68032

Other (OTH) AF: 0.0426 AC: 90 AN: 2112

Alfa AF: 0.0233 Hom.: 73

Bravo AF: 0.0309

Asia WGS AF: 0.0190 AC: 67 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.076
DANN	Benign	0.66
PhyloP100		-2.2
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: rs12722525; hg19: chr10-6077820; COSMIC: COSV56921918; COSMIC: COSV56921918;