NM_000417.3:c.367+7G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000417.3(IL2RA):c.367+7G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 1,585,976 control chromosomes in the GnomAD database, including 41,976 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3284 hom., cov: 33)

Exomes 𝑓: 0.23 ( 38692 hom. )

Consequence

IL2RA
NM_000417.3 splice_region, intron

Scores

Splicing: ADA: 0.00004377

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 0.0900

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 10-6024237-C-G is Benign according to our data. Variant chr10-6024237-C-G is described in ClinVar as Benign. ClinVar VariationId is 300259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
IL2RA	NM_000417.3	MANE Select	c.367+7G>C	splice_region intron	N/A	NP_000408.1
IL2RA	NM_001308242.2		c.367+7G>C	splice_region intron	N/A	NP_001295171.1
IL2RA	NM_001308243.2		c.367+7G>C	splice_region intron	N/A	NP_001295172.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
IL2RA	ENST00000379959.8	TSL:1 MANE Select	c.367+7G>C	splice_region intron	N/A	ENSP00000369293.3
IL2RA	ENST00000379954.5	TSL:1	c.367+7G>C	splice_region intron	N/A	ENSP00000369287.1
IL2RA	ENST00000447847.2	TSL:1	c.367+7G>C	splice_region intron	N/A	ENSP00000402024.2

Frequencies

GnomAD3 genomes

AF:

0.188

AC:

28526

AN:

152094

Hom.:

3278

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0824

Gnomad AMI

AF:

0.260

Gnomad AMR

AF:

0.137

Gnomad ASJ

AF:

0.159

Gnomad EAS

AF:

0.247

Gnomad SAS

AF:

0.239

Gnomad FIN

AF:

0.333

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.233

Gnomad OTH

AF:

0.176

GnomAD2 exomes

AF:

0.211

AC:

52998

AN:

251124

AF XY:

0.217

show subpopulations

Gnomad AFR exome

AF:

0.0806

Gnomad AMR exome

AF:

0.115

Gnomad ASJ exome

AF:

0.149

Gnomad EAS exome

AF:

0.249

Gnomad FIN exome

AF:

0.319

Gnomad NFE exome

AF:

0.231

Gnomad OTH exome

AF:

0.214

GnomAD4 exome

AF:

0.227

AC:

325798

AN:

1433764

Hom.:

38692

Cov.:

AF XY:

0.228

AC XY:

163003

AN XY:

715178

show subpopulations

African (AFR)

AF:

0.0752

AC:

2475

AN:

32912

American (AMR)

AF:

0.117

AC:

5205

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.151

AC:

3912

AN:

25956

East Asian (EAS)

AF:

0.249

AC:

9855

AN:

39524

South Asian (SAS)

AF:

0.237

AC:

20272

AN:

85706

European-Finnish (FIN)

AF:

0.321

AC:

17140

AN:

53400

Middle Eastern (MID)

AF:

0.201

AC:

1148

AN:

5720

European-Non Finnish (NFE)

AF:

0.233

AC:

252796

AN:

1086468

Other (OTH)

AF:

0.219

AC:

12995

AN:

59400

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

11896

23792

35687

47583

59479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8454

16908

25362

33816

42270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.188

AC:

28545

AN:

152212

Hom.:

3284

Cov.:

AF XY:

0.191

AC XY:

14226

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0825

AC:

3429

AN:

41550

American (AMR)

AF:

0.137

AC:

2090

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.159

AC:

553

AN:

3470

East Asian (EAS)

AF:

0.247

AC:

1278

AN:

5172

South Asian (SAS)

AF:

0.241

AC:

1161

AN:

4824

European-Finnish (FIN)

AF:

0.333

AC:

3518

AN:

10580

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.233

AC:

15858

AN:

68000

Other (OTH)

AF:

0.179

AC:

379

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1150

2299

3449

4598

5748

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

320

640

960

1280

1600

<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:

0.186

Hom.:

1002

Bravo

AF:

0.166

Asia WGS

AF:

0.259

AC:

903

AN:

3478

EpiCase

AF:

0.219

EpiControl

AF:

0.216

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency due to CD25 deficiency (3)

not specified (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

1.2

(source)

DANN

Benign

0.70

PhyloP100

0.090

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000044

dbscSNV1_RF

Benign

0.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over