rs12358961

Variant names:

• chr10-6024232-T-A
• rs12358961
• NM_000417.3:c.367+12A>T

Your query was ambiguous. Multiple possible variants found:

• chr10-6024232-T-A
• chr10-6024232-T-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+12A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 1,567,342 control chromosomes in the GnomAD database, including 105,437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8576 hom., cov: 32)
  • Exomes 𝑓: 0.36 (96861 hom.)
• Consequence: IL2RA NM_000417.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.04
• Publications: 18 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=-0.79).
• BP6: Variant 10-6024232-T-A is Benign according to our data. Variant chr10-6024232-T-A is described in ClinVar as Benign. ClinVar VariationId is 300258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RA	NM_000417.3	c.367+12A>T		intron_variant	Intron 3 of 7	ENST00000379959.8	NP_000408.1
IL2RA	NM_001308242.2	c.367+12A>T		intron_variant	Intron 3 of 6		NP_001295171.1
IL2RA	NM_001308243.2	c.367+12A>T		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+12A>T		intron_variant	Intron 3 of 7	1	NM_000417.3	ENSP00000369293.3

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47798 AN: 152028 Hom.: 8561 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.458

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.397

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.356

GnomAD2 exomes AF: 0.375 AC: 94088 AN: 250952 AF XY: 0.368

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.600

Gnomad ASJ exome AF: 0.407

Gnomad EAS exome AF: 0.385

Gnomad FIN exome AF: 0.331

Gnomad NFE exome AF: 0.369

Gnomad OTH exome AF: 0.375

GnomAD4 exome AF: 0.363 AC: 514255 AN: 1415196 Hom.: 96861 Cov.: 25 AF XY: 0.362 AC XY: 255922 AN XY: 707140

African (AFR) AF: 0.131 AC: 4274 AN: 32548

American (AMR) AF: 0.584 AC: 26089 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 10469 AN: 25828

East Asian (EAS) AF: 0.431 AC: 16990 AN: 39442

South Asian (SAS) AF: 0.283 AC: 24182 AN: 85328

European-Finnish (FIN) AF: 0.325 AC: 17365 AN: 53386

Middle Eastern (MID) AF: 0.362 AC: 2057 AN: 5678

European-Non Finnish (NFE) AF: 0.367 AC: 392406 AN: 1069562

Other (OTH) AF: 0.347 AC: 20423 AN: 58788

GnomAD4 genome AF: 0.314 AC: 47831 AN: 152146 Hom.: 8576 Cov.: 32 AF XY: 0.316 AC XY: 23527 AN XY: 74364

African (AFR) AF: 0.148 AC: 6153 AN: 41534

American (AMR) AF: 0.459 AC: 7018 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 1415 AN: 3468

East Asian (EAS) AF: 0.397 AC: 2054 AN: 5168

South Asian (SAS) AF: 0.293 AC: 1412 AN: 4824

European-Finnish (FIN) AF: 0.332 AC: 3519 AN: 10586

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.369 AC: 25061 AN: 67974

Other (OTH) AF: 0.354 AC: 747 AN: 2110

Alfa AF: 0.350 Hom.: 1946

Bravo AF: 0.324

Asia WGS AF: 0.298 AC: 1038 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency due to CD25 deficiency Benign:2

Jan 12, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

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 79% of patients studied by a panel of primary immunodeficiencies. Number of patients: 76. Only high quality variants are reported. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.053
DANN	Benign	0.78
PhyloP100		-1.0
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12358961; hg19: chr10-6066195; COSMIC: COSV56920118; COSMIC: COSV56920118;