chr10-6013187-T-C

Variant names:

• chr10-6013187-T-C
• rs12722598
• NM_000417.3:c.795-291A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000417.3(IL2RA):​c.795-291A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00844 in 152,272 control chromosomes in the GnomAD database, including 7 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 0.0084 (7 hom., cov: 32)
• Consequence: IL2RA NM_000417.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.83
• Publications: 3 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=-0.89).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00844 (1285/152272) while in subpopulation NFE AF = 0.0137 (932/68022). AF 95% confidence interval is 0.013. There are 7 homozygotes in GnomAd4. There are 599 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RA	NM_000417.3	c.795-291A>G		intron_variant	Intron 7 of 7	ENST00000379959.8	NP_000408.1
IL2RA	NM_001308242.2	c.579-291A>G		intron_variant	Intron 6 of 6		NP_001295171.1
IL2RA	NM_001308243.2	c.507-291A>G		intron_variant	Intron 5 of 5		NP_001295172.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL2RA	ENST00000379959.8	c.795-291A>G		intron_variant	Intron 7 of 7	1	NM_000417.3	ENSP00000369293.3

Frequencies

GnomAD3 genomes AF: 0.00845 AC: 1286 AN: 152154 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.00959

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

GnomAD4 genome AF: 0.00844 AC: 1285 AN: 152272 Hom.: 7 Cov.: 32 AF XY: 0.00804 AC XY: 599 AN XY: 74466

African (AFR) AF: 0.00272 AC: 113 AN: 41548

American (AMR) AF: 0.0112 AC: 171 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4826

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0137 AC: 932 AN: 68022

Other (OTH) AF: 0.00949 AC: 20 AN: 2108

Alfa AF: 0.0120 Hom.: 18

Bravo AF: 0.00846

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	8.3
DANN	Benign	0.85
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism

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: rs12722598; hg19: chr10-6055150;