chr10-6019818-T-C

Variant names:

• chr10-6019818-T-C
• rs10752175
• NM_000417.3:c.655+52A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000417.3(IL2RA):​c.655+52A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.896 in 1,533,098 control chromosomes in the GnomAD database, including 619,163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.86 (56906 hom., cov: 32)
  • Exomes 𝑓: 0.90 (562257 hom.)
• Consequence: IL2RA NM_000417.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0510
• Publications: 11 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

LOC124902368 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 10-6019818-T-C is Benign according to our data. Variant chr10-6019818-T-C is described in ClinVar as Benign. ClinVar VariationId is 2628287.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.917 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RA	NM_000417.3	MANE Select	c.655+52A>G		intron	N/A	NP_000408.1
	IL2RA	NM_001308242.2		c.439+52A>G		intron	N/A	NP_001295171.1
	IL2RA	NM_001308243.2		c.368-319A>G		intron	N/A	NP_001295172.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RA	ENST00000379959.8	TSL:1 MANE Select	c.655+52A>G		intron	N/A	ENSP00000369293.3
	IL2RA	ENST00000379954.5	TSL:1	c.439+52A>G		intron	N/A	ENSP00000369287.1
	IL2RA	ENST00000447847.2	TSL:1	c.368-319A>G		intron	N/A	ENSP00000402024.2

Frequencies

GnomAD3 genomes AF: 0.862 AC: 131030 AN: 152034 Hom.: 56856 Cov.: 32

Gnomad AFR AF: 0.828

Gnomad AMI AF: 0.962

Gnomad AMR AF: 0.738

Gnomad ASJ AF: 0.926

Gnomad EAS AF: 0.749

Gnomad SAS AF: 0.856

Gnomad FIN AF: 0.802

Gnomad MID AF: 0.924

Gnomad NFE AF: 0.923

Gnomad OTH AF: 0.873

GnomAD4 exome AF: 0.900 AC: 1243023 AN: 1380946 Hom.: 562257 Cov.: 21 AF XY: 0.900 AC XY: 622453 AN XY: 691396

African (AFR) AF: 0.828 AC: 26341 AN: 31796

American (AMR) AF: 0.658 AC: 29368 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.929 AC: 23822 AN: 25646

East Asian (EAS) AF: 0.772 AC: 30347 AN: 39302

South Asian (SAS) AF: 0.861 AC: 72917 AN: 84664

European-Finnish (FIN) AF: 0.816 AC: 43541 AN: 53380

Middle Eastern (MID) AF: 0.903 AC: 5066 AN: 5608

European-Non Finnish (NFE) AF: 0.925 AC: 960287 AN: 1038232

Other (OTH) AF: 0.890 AC: 51334 AN: 57700

GnomAD4 genome AF: 0.862 AC: 131128 AN: 152152 Hom.: 56906 Cov.: 32 AF XY: 0.854 AC XY: 63517 AN XY: 74358

African (AFR) AF: 0.828 AC: 34361 AN: 41486

American (AMR) AF: 0.738 AC: 11279 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.926 AC: 3215 AN: 3472

East Asian (EAS) AF: 0.748 AC: 3875 AN: 5178

South Asian (SAS) AF: 0.856 AC: 4123 AN: 4814

European-Finnish (FIN) AF: 0.802 AC: 8498 AN: 10590

Middle Eastern (MID) AF: 0.935 AC: 273 AN: 292

European-Non Finnish (NFE) AF: 0.923 AC: 62795 AN: 68012

Other (OTH) AF: 0.869 AC: 1834 AN: 2110

Alfa AF: 0.891 Hom.: 8256

Bravo AF: 0.851

Asia WGS AF: 0.784 AC: 2728 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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 89% of patients studied by a panel of primary immunodeficiencies. Number of patients: 85. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.6
DANN	Benign	0.35
PhyloP100		0.051
Mutation Taster		=100/0	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: rs10752175; hg19: chr10-6061781;