NM_000417.3:c.64+3326C>T

Variant names:

• chr10-6058762-G-A
• rs3134883
• NM_000417.3:c.64+3326C>T

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+3326C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.23 (AC=34,947) in the gnomAD database across 152,084 control chromosomes, including 5,027 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.303. 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 0.23 (5027 hom., cov: 32)
• Consequence: IL2RA NM_000417.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.244
• Publications: 32 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 = 0.3031 — 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+3326C>T	intron	Intron 1 of 7	Prot: NP_000408.1 UniProt:
	IL2RA NM_001308242.2		c.64+3326C>T	intron	Intron 1 of 6	Prot: NP_001295171.1 UniProt:
	IL2RA NM_001308243.2		c.64+3326C>T	intron	Intron 1 of 5	Prot: NP_001295172.1 UniProt:

IL2RA NM_000417.3

MANE Select

HGVSc / HGVSpc.64+3326C>T

Exon rankIntron 1 of 7

intron

Prot: NP_000408.1UniProt: P01589

IL2RA NM_001308242.2

HGVSc / HGVSpc.64+3326C>T

Exon rankIntron 1 of 6

intron

Prot: NP_001295171.1UniProt: Q5W005

IL2RA NM_001308243.2

HGVSc / HGVSpc.64+3326C>T

Exon rankIntron 1 of 5

intron

Prot: NP_001295172.1UniProt: H0Y5Z0

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	IL2RA ENST00000379959.8	TSL:1MANE Select	c.64+3326C>T	intron	Intron 1 of 7	Prot: ENSP00000369293.3 UniProt:
	IL2RA ENST00000379954.5	TSL:1	c.64+3326C>T	intron	Intron 1 of 6	Prot: ENSP00000369287.1 UniProt:
	IL2RA ENST00000447847.2	TSL:1	c.64+3326C>T	intron	Intron 1 of 5	Prot: ENSP00000402024.2 UniProt:

IL2RA ENST00000379959.8

TSL:1MANE Select

HGVSc / HGVSpc.64+3326C>T

Exon rankIntron 1 of 7

intron

Prot: ENSP00000369293.3UniProt: P01589

IL2RA ENST00000379954.5

TSL:1

HGVSc / HGVSpc.64+3326C>T

Exon rankIntron 1 of 6

intron

Prot: ENSP00000369287.1UniProt: Q5W005

IL2RA ENST00000447847.2

TSL:1

HGVSc / HGVSpc.64+3326C>T

Exon rankIntron 1 of 5

intron

Prot: ENSP00000402024.2UniProt: 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: 0.230	AC:34935	Hom:5020	AN:151964	Cov:32
GnomAD4 genome	AF: 0.230	AC:34947	Hom:5027	AN:152084	Cov:32
TOPMed (Bravo)	AF: 0.207	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.289	AC:26864	Hom:4177	AN:93052	Cov:
Local & regional cohorts 9 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.204	AC:478	Hom:55	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.277	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.310	AC:93	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.277	AC:966	Hom:	AN:3476	Cov:
Korea4K (4,157 Koreans)	AF: 0.283	AC:2044	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.267	AC:47	Hom:	AN:176	Cov:
Turkish Variome	AF: 0.323	AC:500	Hom:80	AN:1546	Cov:
UK10K	AF: 0.306	AC:2315	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.259	AC:2323	Hom:335	AN:8960	Cov:

Showing 13 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	1.1
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.7
DANN	Benign	0.55
GPN-Star LLR	N/A	-1.6
GPN-Star score	N/A	1.6
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-0.24

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs3134883;

hg19: chr10-6100725;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar