chr10-6046780-A-T

Variant names:

• chr10-6046780-A-T
• rs12722508
• NM_000417.3:c.64+15308T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000417.3(IL2RA):​c.64+15308T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0685 in 152,274 control chromosomes in the GnomAD database, including 487 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.069 (487 hom., cov: 32)
• Consequence: IL2RA NM_000417.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.50
• Publications: 11 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 10-6046780-A-T is Benign according to our data. Variant chr10-6046780-A-T is described in ClinVar as Benign. ClinVar VariationId is 465830.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.102 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RA	NM_000417.3	MANE Select	c.64+15308T>A		intron	N/A	NP_000408.1
	IL2RA	NM_001308242.2		c.64+15308T>A		intron	N/A	NP_001295171.1
	IL2RA	NM_001308243.2		c.64+15308T>A		intron	N/A	NP_001295172.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RA	ENST00000379959.8	TSL:1 MANE Select	c.64+15308T>A		intron	N/A	ENSP00000369293.3
	IL2RA	ENST00000379954.5	TSL:1	c.64+15308T>A		intron	N/A	ENSP00000369287.1
	IL2RA	ENST00000447847.2	TSL:1	c.64+15308T>A		intron	N/A	ENSP00000402024.2

Frequencies

GnomAD3 genomes AF: 0.0686 AC: 10434 AN: 152156 Hom.: 487 Cov.: 32

Gnomad AFR AF: 0.0181

Gnomad AMI AF: 0.165

Gnomad AMR AF: 0.0504

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0774

Gnomad FIN AF: 0.0671

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0651

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

GnomAD4 genome AF: 0.0685 AC: 10431 AN: 152274 Hom.: 487 Cov.: 32 AF XY: 0.0664 AC XY: 4947 AN XY: 74458

African (AFR) AF: 0.0180 AC: 750 AN: 41564

American (AMR) AF: 0.0504 AC: 771 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 432 AN: 3468

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5184

South Asian (SAS) AF: 0.0781 AC: 377 AN: 4826

European-Finnish (FIN) AF: 0.0671 AC: 712 AN: 10612

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7072 AN: 67998

Other (OTH) AF: 0.0640 AC: 135 AN: 2110

Alfa AF: 0.0320 Hom.: 29

Bravo AF: 0.0651

Asia WGS AF: 0.0220 AC: 76 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Immunodeficiency due to CD25 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.7
DANN	Benign	0.80
PhyloP100		-1.5
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: rs12722508; hg19: chr10-6088743;