rs3134883

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr10-6058762-G-A
• chr10-6058762-G-C

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	N/A	NP_000408.1	P01589
	IL2RA	NM_001308242.2		c.64+3326C>T		intron	N/A	NP_001295171.1	Q5W005
	IL2RA	NM_001308243.2		c.64+3326C>T		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+3326C>T		intron	N/A	ENSP00000369293.3	P01589
	IL2RA	ENST00000379954.5	TSL:1	c.64+3326C>T		intron	N/A	ENSP00000369287.1	Q5W005
	IL2RA	ENST00000447847.2	TSL:1	c.64+3326C>T		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: 0.230	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

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	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.

Other links and lift over

dbSNP: rs3134883;

hg19: chr10-6100725;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar