chr10-6047608-G-A

Variant names:

• chr10-6047608-G-A
• rs791589
• NM_000417.3:c.64+14480C>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.64+14480C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 151,086 control chromosomes in the GnomAD database, including 41,169 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 0.71 (41169 hom., cov: 30)
• Consequence: IL2RA NM_000417.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.506
• Publications: 20 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=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RA	NM_000417.3	c.64+14480C>T		intron_variant	Intron 1 of 7	ENST00000379959.8	NP_000408.1
IL2RA	NM_001308242.2	c.64+14480C>T		intron_variant	Intron 1 of 6		NP_001295171.1
IL2RA	NM_001308243.2	c.64+14480C>T		intron_variant	Intron 1 of 5		NP_001295172.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL2RA	ENST00000379959.8	c.64+14480C>T		intron_variant	Intron 1 of 7	1	NM_000417.3	ENSP00000369293.3

Frequencies

GnomAD3 genomes AF: 0.710 AC: 107176 AN: 151004 Hom.: 41157 Cov.: 30

Gnomad AFR AF: 0.398

Gnomad AMI AF: 0.909

Gnomad AMR AF: 0.699

Gnomad ASJ AF: 0.851

Gnomad EAS AF: 0.657

Gnomad SAS AF: 0.823

Gnomad FIN AF: 0.863

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.862

Gnomad OTH AF: 0.734

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

GnomAD4 genome AF: 0.710 AC: 107204 AN: 151086 Hom.: 41169 Cov.: 30 AF XY: 0.711 AC XY: 52485 AN XY: 73852

African (AFR) AF: 0.399 AC: 16391 AN: 41120

American (AMR) AF: 0.698 AC: 10589 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.851 AC: 2951 AN: 3468

East Asian (EAS) AF: 0.656 AC: 3382 AN: 5152

South Asian (SAS) AF: 0.825 AC: 3958 AN: 4798

European-Finnish (FIN) AF: 0.863 AC: 8818 AN: 10218

Middle Eastern (MID) AF: 0.746 AC: 212 AN: 284

European-Non Finnish (NFE) AF: 0.863 AC: 58536 AN: 67866

Other (OTH) AF: 0.734 AC: 1538 AN: 2094

Alfa AF: 0.816 Hom.: 80489

Bravo AF: 0.680

Asia WGS AF: 0.758 AC: 2632 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.64
DANN	Benign	0.74
PhyloP100		-0.51
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: rs791589; hg19: chr10-6089571;