10-6040990-G-T

Variant names:

• chr10-6040990-G-T
• rs6602398
• NM_000417.3:c.65-14965C>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.65-14965C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 152,086 control chromosomes in the GnomAD database, including 4,950 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 0.22 (4950 hom., cov: 33)
• Consequence: IL2RA NM_000417.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.376
• Publications: 29 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.314 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.65-14965C>A		intron	N/A	NP_000408.1
	IL2RA	NM_001308242.2		c.65-14965C>A		intron	N/A	NP_001295171.1
	IL2RA	NM_001308243.2		c.65-14965C>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.65-14965C>A		intron	N/A	ENSP00000369293.3
	IL2RA	ENST00000379954.5	TSL:1	c.65-14965C>A		intron	N/A	ENSP00000369287.1
	IL2RA	ENST00000447847.2	TSL:1	c.65-14965C>A		intron	N/A	ENSP00000402024.2

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34165 AN: 151968 Hom.: 4946 Cov.: 33

Gnomad AFR AF: 0.0609

Gnomad AMI AF: 0.297

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.0248

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.261

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

GnomAD4 genome AF: 0.225 AC: 34165 AN: 152086 Hom.: 4950 Cov.: 33 AF XY: 0.222 AC XY: 16518 AN XY: 74366

African (AFR) AF: 0.0607 AC: 2519 AN: 41510

American (AMR) AF: 0.247 AC: 3772 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 1216 AN: 3466

East Asian (EAS) AF: 0.0248 AC: 129 AN: 5192

South Asian (SAS) AF: 0.197 AC: 952 AN: 4828

European-Finnish (FIN) AF: 0.290 AC: 3060 AN: 10538

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.318 AC: 21606 AN: 67958

Other (OTH) AF: 0.262 AC: 553 AN: 2110

Alfa AF: 0.296 Hom.: 10841

Bravo AF: 0.216

Asia WGS AF: 0.133 AC: 461 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.2
DANN	Benign	0.55
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: rs6602398; hg19: chr10-6082953;