rs12722489

Variant names:

• chr10-6060049-C-T
• rs12722489
• NM_000417.3:c.64+2039G>A

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_000417.3(IL2RA):c.64+2039G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.106 (AC=16,152) in the gnomAD database across 152,076 control chromosomes, including 1,103 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.153. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (1103 hom., cov: 31)
• Consequence: IL2RA NM_000417.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0320
• Publications: 112 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: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, 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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

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

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1527 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000417.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RA	NM_000417.3	MANE Select	c.64+2039G>A		intron	N/A	NP_000408.1	P01589
	IL2RA	NM_001308242.2		c.64+2039G>A		intron	N/A	NP_001295171.1	Q5W005
	IL2RA	NM_001308243.2		c.64+2039G>A		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.64+2039G>A		intron	N/A	ENSP00000369293.3	P01589
	IL2RA	ENST00000379954.5	TSL:1	c.64+2039G>A		intron	N/A	ENSP00000369287.1	Q5W005
	IL2RA	ENST00000447847.2	TSL:1	c.64+2039G>A		intron	N/A	ENSP00000402024.2	H0Y5Z0

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.106	AC:16165	Hom:1107	AN:151958	Cov:31
GnomAD4 genome	AF: 0.106	AC:16152	Hom:1103	AN:152076	Cov:31
TOPMed (Bravo)	AF: 0.0995	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.138	AC:90032	Hom:6719	AN:651304	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0956	AC:224	Hom:13	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.129	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.173	AC:52	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.141	AC:490	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.109	AC:785	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.0398	AC:7	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.103	AC:12620	Hom:679	AN:122696	Cov:
Turkish Variome	AF: 0.0724	AC:112	Hom:7	AN:1546	Cov:
UK10K	AF: 0.163	AC:1234	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.137	AC:1224	Hom:100	AN:8960	Cov:

Showing 14 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.65
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.53
GPN-Star LLR	N/A	0.35
GPN-Star score	N/A	-0.35
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	0.032

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs12722489;

hg19: chr10-6102012;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar