rs12358961

chr10-6024232-T-Achr10-6024232-T-C

Variant summary

Our verdict is Benign. Variant got -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:3
• Conservation: PhyloP100: -1.04

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 300258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-6024232-T-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
IL2RA	NM_000417.3	c.367+12A>T		intron_variant		ENST00000379959.8
IL2RA	NM_001308242.2	c.367+12A>T		intron_variant
IL2RA	NM_001308243.2	c.367+12A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL2RA	ENST00000379959.8	c.367+12A>T		intron_variant		1	NM_000417.3	P1

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

GnomAD3 exomes AF: 0.375 AC: 94088 AN: 250952 Hom.: 19245 AF XY: 0.368 AC XY: 49971 AN XY: 135652

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 SAS exome AF: 0.284

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

Gnomad4 AFR exome AF: 0.131

Gnomad4 AMR exome AF: 0.584

Gnomad4 ASJ exome AF: 0.405

Gnomad4 EAS exome AF: 0.431

Gnomad4 SAS exome AF: 0.283

Gnomad4 FIN exome AF: 0.325

Gnomad4 NFE exome AF: 0.367

Gnomad4 OTH exome AF: 0.347

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

Gnomad4 AFR AF: 0.148

Gnomad4 AMR AF: 0.459

Gnomad4 ASJ AF: 0.408

Gnomad4 EAS AF: 0.397

Gnomad4 SAS AF: 0.293

Gnomad4 FIN AF: 0.332

Gnomad4 NFE AF: 0.369

Gnomad4 OTH AF: 0.354

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency due to CD25 deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.053
Dann	Benign	0.78

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

LitVar

Other links and lift over

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