rs2025345

Positions:

• chr10-6025725-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000417.3(IL2RA):​c.256+109T>C 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 1,028,996 control chromosomes in the GnomAD database, including 70,040 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.31 (8522 hom., cov: 32)
  • Exomes 𝑓: 0.37 (61518 hom.)
• Consequence: IL2RA NM_000417.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.189

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 10-6025725-A-G is Benign according to our data. Variant chr10-6025725-A-G is described in ClinVar as [Benign]. Clinvar id is 2688212.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL2RA	NM_000417.3	c.256+109T>C		intron_variant		ENST00000379959.8
IL2RA	NM_001308242.2	c.256+109T>C		intron_variant
IL2RA	NM_001308243.2	c.256+109T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL2RA	ENST00000379959.8	c.256+109T>C		intron_variant		1	NM_000417.3	P1

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47656 AN: 151824 Hom.: 8506 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.352

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.394

Gnomad SAS AF: 0.292

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.368

Gnomad OTH AF: 0.357

GnomAD4 exome AF: 0.367 AC: 322098 AN: 877058 Hom.: 61518 AF XY: 0.364 AC XY: 166469 AN XY: 457254

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.579

Gnomad4 ASJ exome AF: 0.403

Gnomad4 EAS exome AF: 0.435

Gnomad4 SAS exome AF: 0.284

Gnomad4 FIN exome AF: 0.324

Gnomad4 NFE exome AF: 0.371

Gnomad4 OTH exome AF: 0.351

GnomAD4 genome AF: 0.314 AC: 47691 AN: 151938 Hom.: 8522 Cov.: 32 AF XY: 0.316 AC XY: 23456 AN XY: 74234

Gnomad4 AFR AF: 0.148

Gnomad4 AMR AF: 0.456

Gnomad4 ASJ AF: 0.409

Gnomad4 EAS AF: 0.395

Gnomad4 SAS AF: 0.292

Gnomad4 FIN AF: 0.334

Gnomad4 NFE AF: 0.368

Gnomad4 OTH AF: 0.355

Alfa AF: 0.371 Hom.: 15638

Bravo AF: 0.322

Asia WGS AF: 0.297 AC: 1033 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 34% of patients studied by a panel of primary immunodeficiencies. Number of patients: 32. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.8
DANN	Benign	0.72

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: rs2025345; hg19: chr10-6067688; COSMIC: COSV56920579; COSMIC: COSV56920579;