dbSNP rs6602392: IL2RA:c.65-10091G>T (chr10-6036116-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000417.3(IL2RA):c.65-10091G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 152,220 control chromosomes in the GnomAD database, including 2,319 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.16 ( 2319 hom., cov: 32)

Exomes 𝑓: 0.036 ( 0 hom. )

Consequence

IL2RA
NM_000417.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.137

Publications

16 publications found

Variant links:

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

IL2RA links:

ENSG00000229664 (HGNC:58167):

ENSG00000229664 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
IL2RA	NM_000417.3 link	c.65-10091G>T	intron_variant	Intron 1 of 7	ENST00000379959.8	NP_000408.1	P01589
IL2RA	NM_001308242.2 link	c.65-10091G>T	intron_variant	Intron 1 of 6		NP_001295171.1	P01589Q5W005
IL2RA	NM_001308243.2 link	c.65-10091G>T	intron_variant	Intron 1 of 5		NP_001295172.1	P01589H0Y5Z0
IL2RA-AS1	XR_001747349.2 link	n.653+54C>A	intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL2RA	ENST00000379959.8 link	c.65-10091G>T		intron_variant	Intron 1 of 7	1	NM_000417.3	ENSP00000369293.3		P01589

Frequencies

GnomAD3 genomes

AF:

0.156

AC:

23716

AN:

152074

Hom.:

2312

Cov.:

show subpopulations

Gnomad AFR

AF:

0.238

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.160

Gnomad ASJ

AF:

0.168

Gnomad EAS

AF:

0.316

Gnomad SAS

AF:

0.163

Gnomad FIN

AF:

0.0684

Gnomad MID

AF:

0.268

Gnomad NFE

AF:

0.106

Gnomad OTH

AF:

0.164

GnomAD4 exome

AF:

0.0357

AC:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0455

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.156

AC:

23755

AN:

152192

Hom.:

2319

Cov.:

AF XY:

0.156

AC XY:

11644

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.238

AC:

9864

AN:

41492

American (AMR)

AF:

0.161

AC:

2462

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.168

AC:

583

AN:

3472

East Asian (EAS)

AF:

0.316

AC:

1637

AN:

5176

South Asian (SAS)

AF:

0.163

AC:

784

AN:

4820

European-Finnish (FIN)

AF:

0.0684

AC:

726

AN:

10614

Middle Eastern (MID)

AF:

0.281

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.106

AC:

7236

AN:

68008

Other (OTH)

AF:

0.163

AC:

343

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1002

2003

3005

4006

5008

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

260

520

780

1040

1300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.122

Hom.:

2485

Bravo

AF:

0.165

Asia WGS

AF:

0.188

AC:

655

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.0

(source)

DANN

Benign

0.77

PhyloP100

-0.14

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over