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: 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

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RA	NM_000417.3	c.*1549C>T		3_prime_UTR_variant	Exon 8 of 8	ENST00000379959.8	NP_000408.1
IL2RA	NM_001308242.2	c.*1549C>T		3_prime_UTR_variant	Exon 7 of 7		NP_001295171.1
IL2RA	NM_001308243.2	c.*1549C>T		3_prime_UTR_variant	Exon 6 of 6		NP_001295172.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL2RA	ENST00000379959.8	c.*1549C>T		3_prime_UTR_variant	Exon 8 of 8	1	NM_000417.3	ENSP00000369293.3
IL2RA	ENST00000649218.1	n.2183C>T		non_coding_transcript_exon_variant	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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency due to CD25 deficiency Benign:1

Jan 12, 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 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	-0.87
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;