10-6044329-G-T

Variant names:

• chr10-6044329-G-T
• rs942201
• NM_000417.3:c.64+17759C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000417.3(IL2RA):​c.64+17759C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 152,254 control chromosomes in the GnomAD database, including 3,104 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (3104 hom., cov: 33)
• Consequence: IL2RA NM_000417.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.44
• Publications: 17 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.254 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.64+17759C>A		intron	N/A	NP_000408.1
	IL2RA	NM_001308242.2		c.64+17759C>A		intron	N/A	NP_001295171.1
	IL2RA	NM_001308243.2		c.64+17759C>A		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.64+17759C>A		intron	N/A	ENSP00000369293.3
	IL2RA	ENST00000379954.5	TSL:1	c.64+17759C>A		intron	N/A	ENSP00000369287.1
	IL2RA	ENST00000447847.2	TSL:1	c.64+17759C>A		intron	N/A	ENSP00000402024.2

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28547 AN: 152136 Hom.: 3100 Cov.: 33

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.271

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.181

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.188 AC: 28564 AN: 152254 Hom.: 3104 Cov.: 33 AF XY: 0.189 AC XY: 14094 AN XY: 74442

African (AFR) AF: 0.106 AC: 4410 AN: 41548

American (AMR) AF: 0.147 AC: 2252 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 483 AN: 3472

East Asian (EAS) AF: 0.266 AC: 1377 AN: 5184

South Asian (SAS) AF: 0.235 AC: 1135 AN: 4828

European-Finnish (FIN) AF: 0.271 AC: 2872 AN: 10588

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15338 AN: 68018

Other (OTH) AF: 0.186 AC: 394 AN: 2116

Alfa AF: 0.197 Hom.: 1923

Bravo AF: 0.172

Asia WGS AF: 0.274 AC: 953 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.099
DANN	Benign	0.51
PhyloP100		-1.4
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: rs942201; hg19: chr10-6086292;