10-6024237-C-G

Variant names:

• chr10-6024237-C-G
• rs11256369
• NM_000417.3:c.367+7G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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:6 O:1
• Conservation: PhyloP100: 0.0900
• Publications: 16 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: 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

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RA	NM_000417.3	c.367+7G>C		splice_region_variant, intron_variant	Intron 3 of 7	ENST00000379959.8	NP_000408.1
IL2RA	NM_001308242.2	c.367+7G>C		splice_region_variant, intron_variant	Intron 3 of 6		NP_001295171.1
IL2RA	NM_001308243.2	c.367+7G>C		splice_region_variant, intron_variant	Intron 3 of 5		NP_001295172.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL2RA	ENST00000379959.8	c.367+7G>C		splice_region_variant, intron_variant	Intron 3 of 7	1	NM_000417.3	ENSP00000369293.3

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28526 AN: 152094 Hom.: 3278 Cov.: 33

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

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.: 28 AF XY: 0.228 AC XY: 163003 AN XY: 715178

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

GnomAD4 genome AF: 0.188 AC: 28545 AN: 152212 Hom.: 3284 Cov.: 33 AF XY: 0.191 AC XY: 14226 AN XY: 74394

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: 42 AN: 294

European-Non Finnish (NFE) AF: 0.233 AC: 15858 AN: 68000

Other (OTH) AF: 0.179 AC: 379 AN: 2112

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

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency due to CD25 deficiency Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 19. Only high quality variants are reported. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.2
DANN	Benign	0.70
PhyloP100		0.090
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11256369; hg19: chr10-6066200; COSMIC: COSV56920923; COSMIC: COSV56920923;