10-6048359-A-T

Variant names:

• chr10-6048359-A-T
• rs791590
• NM_000417.3:c.64+13729T>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+13729T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 152,238 control chromosomes in the GnomAD database, including 1,321 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 0.12 (1321 hom., cov: 33)
• Consequence: IL2RA NM_000417.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.378
• Publications: 21 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.154 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+13729T>A		intron	N/A	NP_000408.1
	IL2RA	NM_001308242.2		c.64+13729T>A		intron	N/A	NP_001295171.1
	IL2RA	NM_001308243.2		c.64+13729T>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+13729T>A		intron	N/A	ENSP00000369293.3
	IL2RA	ENST00000379954.5	TSL:1	c.64+13729T>A		intron	N/A	ENSP00000369287.1
	IL2RA	ENST00000447847.2	TSL:1	c.64+13729T>A		intron	N/A	ENSP00000402024.2

Frequencies

GnomAD3 genomes AF: 0.125 AC: 19036 AN: 152120 Hom.: 1324 Cov.: 33

Gnomad AFR AF: 0.0932

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.0785

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.109

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

GnomAD4 genome AF: 0.125 AC: 19023 AN: 152238 Hom.: 1321 Cov.: 33 AF XY: 0.121 AC XY: 9009 AN XY: 74470

African (AFR) AF: 0.0929 AC: 3860 AN: 41558

American (AMR) AF: 0.0784 AC: 1199 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 431 AN: 3468

East Asian (EAS) AF: 0.134 AC: 692 AN: 5170

South Asian (SAS) AF: 0.119 AC: 576 AN: 4822

European-Finnish (FIN) AF: 0.118 AC: 1258 AN: 10620

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10651 AN: 67980

Other (OTH) AF: 0.107 AC: 227 AN: 2114

Alfa AF: 0.139 Hom.: 203

Bravo AF: 0.121

Asia WGS AF: 0.133 AC: 464 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.5
DANN	Benign	0.52
PhyloP100		0.38
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: rs791590; hg19: chr10-6090322;