chr10-6017935-C-A

Variant names:

• chr10-6017935-C-A
• rs7899538
• NM_000417.3:c.794+118G>T

Variant summary

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

The NM_000417.3(IL2RA):​c.794+118G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 791,480 control chromosomes in the GnomAD database, including 7,632 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 0.11 (1221 hom., cov: 31)
  • Exomes 𝑓: 0.13 (6411 hom.)
• Consequence: IL2RA NM_000417.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.272
• Publications: 13 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: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.215 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RA	NM_000417.3	MANE Select	c.794+118G>T		intron	N/A	NP_000408.1	P01589
	IL2RA	NM_001308242.2		c.578+118G>T		intron	N/A	NP_001295171.1	Q5W005
	IL2RA	NM_001308243.2		c.506+118G>T		intron	N/A	NP_001295172.1	H0Y5Z0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RA	ENST00000379959.8	TSL:1 MANE Select	c.794+118G>T		intron	N/A	ENSP00000369293.3	P01589
	IL2RA	ENST00000379954.5	TSL:1	c.578+118G>T		intron	N/A	ENSP00000369287.1	Q5W005
	IL2RA	ENST00000447847.2	TSL:1	c.506+118G>T		intron	N/A	ENSP00000402024.2	H0Y5Z0

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17124 AN: 151844 Hom.: 1219 Cov.: 31

Gnomad AFR AF: 0.0589

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.0770

Gnomad ASJ AF: 0.0997

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.100

GnomAD4 exome AF: 0.133 AC: 85285 AN: 639518 Hom.: 6411 AF XY: 0.133 AC XY: 45185 AN XY: 340188

African (AFR) AF: 0.0605 AC: 1037 AN: 17128

American (AMR) AF: 0.0713 AC: 2466 AN: 34592

Ashkenazi Jewish (ASJ) AF: 0.0918 AC: 1857 AN: 20226

East Asian (EAS) AF: 0.218 AC: 7024 AN: 32246

South Asian (SAS) AF: 0.125 AC: 7981 AN: 63838

European-Finnish (FIN) AF: 0.227 AC: 10870 AN: 47812

Middle Eastern (MID) AF: 0.0843 AC: 336 AN: 3988

European-Non Finnish (NFE) AF: 0.128 AC: 49637 AN: 386924

Other (OTH) AF: 0.124 AC: 4077 AN: 32764

GnomAD4 genome AF: 0.113 AC: 17136 AN: 151962 Hom.: 1221 Cov.: 31 AF XY: 0.116 AC XY: 8623 AN XY: 74246

African (AFR) AF: 0.0590 AC: 2447 AN: 41472

American (AMR) AF: 0.0769 AC: 1175 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0997 AC: 346 AN: 3470

East Asian (EAS) AF: 0.226 AC: 1163 AN: 5144

South Asian (SAS) AF: 0.131 AC: 627 AN: 4800

European-Finnish (FIN) AF: 0.227 AC: 2388 AN: 10542

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.126 AC: 8592 AN: 67942

Other (OTH) AF: 0.104 AC: 219 AN: 2110

Alfa AF: 0.115 Hom.: 1869

Bravo AF: 0.0985

Asia WGS AF: 0.205 AC: 713 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.2
DANN	Benign	0.70
PhyloP100		-0.27
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: rs7899538; hg19: chr10-6059898;