10-6011323-G-A

Variant names:

• chr10-6011323-G-A
• rs12722604
• NM_000417.3:c.*1549C>T

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.*1549C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0419 in 152,064 control chromosomes in the GnomAD database, including 359 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (359 hom., cov: 32)
  • Exomes 𝑓: 0.035 (0 hom.)
• Consequence: IL2RA NM_000417.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.543
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 10-6011323-G-A is Benign according to our data. Variant chr10-6011323-G-A is described in ClinVar as Benign. ClinVar VariationId is 300222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.29 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.*1549C>T		3_prime_UTR	Exon 8 of 8	NP_000408.1	P01589
	IL2RA	NM_001308242.2		c.*1549C>T		3_prime_UTR	Exon 7 of 7	NP_001295171.1	Q5W005
	IL2RA	NM_001308243.2		c.*1549C>T		3_prime_UTR	Exon 6 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.*1549C>T		3_prime_UTR	Exon 8 of 8	ENSP00000369293.3	P01589
	IL2RA	ENST00000649218.1		n.2183C>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.0418 AC: 6351 AN: 151804 Hom.: 359 Cov.: 32

Gnomad AFR AF: 0.00961

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0646

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.302

Gnomad SAS AF: 0.0623

Gnomad FIN AF: 0.0505

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0355

Gnomad OTH AF: 0.0404

GnomAD4 exome AF: 0.0352 AC: 5 AN: 142 Hom.: 0 Cov.: 0 AF XY: 0.0256 AC XY: 2 AN XY: 78

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.0362 AC: 5 AN: 138

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

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

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0419 AC: 6364 AN: 151922 Hom.: 359 Cov.: 32 AF XY: 0.0451 AC XY: 3351 AN XY: 74222

African (AFR) AF: 0.00970 AC: 403 AN: 41530

American (AMR) AF: 0.0653 AC: 996 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 73 AN: 3470

East Asian (EAS) AF: 0.303 AC: 1562 AN: 5158

South Asian (SAS) AF: 0.0615 AC: 295 AN: 4796

European-Finnish (FIN) AF: 0.0505 AC: 530 AN: 10492

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0355 AC: 2414 AN: 67908

Other (OTH) AF: 0.0400 AC: 84 AN: 2102

Alfa AF: 0.0352 Hom.: 28

Bravo AF: 0.0432

Asia WGS AF: 0.142 AC: 495 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.51
DANN	Benign	0.50
PhyloP100		-0.54
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: rs12722604; hg19: chr10-6053286;