rs11256456

Variant names:

• chr10-6038749-T-C
• rs11256456
• NM_000417.3:c.65-12724A>G

Variant summary

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

The NM_000417.3(IL2RA):​c.65-12724A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 152,228 control chromosomes in the GnomAD database, including 3,015 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 (3015 hom., cov: 33)
• Consequence: IL2RA NM_000417.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.942
• Publications: 8 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RA	NM_000417.3	c.65-12724A>G		intron_variant	Intron 1 of 7	ENST00000379959.8	NP_000408.1
IL2RA	NM_001308242.2	c.65-12724A>G		intron_variant	Intron 1 of 6		NP_001295171.1
IL2RA	NM_001308243.2	c.65-12724A>G		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.65-12724A>G		intron_variant	Intron 1 of 7	1	NM_000417.3	ENSP00000369293.3

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28780 AN: 152110 Hom.: 3010 Cov.: 33

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.269

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.181

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

GnomAD4 genome AF: 0.189 AC: 28805 AN: 152228 Hom.: 3015 Cov.: 33 AF XY: 0.191 AC XY: 14194 AN XY: 74418

African (AFR) AF: 0.136 AC: 5668 AN: 41538

American (AMR) AF: 0.142 AC: 2175 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 481 AN: 3472

East Asian (EAS) AF: 0.265 AC: 1372 AN: 5184

South Asian (SAS) AF: 0.233 AC: 1124 AN: 4828

European-Finnish (FIN) AF: 0.269 AC: 2847 AN: 10576

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.212 AC: 14444 AN: 68008

Other (OTH) AF: 0.186 AC: 393 AN: 2116

Alfa AF: 0.199 Hom.: 717

Bravo AF: 0.175

Asia WGS AF: 0.273 AC: 952 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.6
DANN	Benign	0.74
PhyloP100		0.94
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: rs11256456; hg19: chr10-6080712;