10-6011605-C-T

Variant names:

• chr10-6011605-C-T
• rs1570538
• NM_000417.3:c.*1267G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000417.3(IL2RA):​c.*1267G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 152,244 control chromosomes in the GnomAD database, including 14,226 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14200 hom., cov: 32)
  • Exomes 𝑓: 0.49 (26 hom.)
• Consequence: IL2RA NM_000417.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.616
• Publications: 10 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: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 10-6011605-C-T is Benign according to our data. Variant chr10-6011605-C-T is described in ClinVar as Benign. ClinVar VariationId is 300226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.505 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.*1267G>A		3_prime_UTR	Exon 8 of 8	NP_000408.1	P01589
	IL2RA	NM_001308242.2		c.*1267G>A		3_prime_UTR	Exon 7 of 7	NP_001295171.1	Q5W005
	IL2RA	NM_001308243.2		c.*1267G>A		3_prime_UTR	Exon 6 of 6	NP_001295172.1	H0Y5Z0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RA	ENST00000379959.8	TSL:1 MANE Select	c.*1267G>A		3_prime_UTR	Exon 8 of 8	ENSP00000369293.3	P01589
	IL2RA	ENST00000649218.1		n.1901G>A		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63430 AN: 151906 Hom.: 14195 Cov.: 32

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.616

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.489

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.419

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.422

GnomAD4 exome AF: 0.491 AC: 108 AN: 220 Hom.: 26 Cov.: 0 AF XY: 0.488 AC XY: 81 AN XY: 166

African (AFR) AF: 0.500 AC: 3 AN: 6

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AF: 0.500 AC: 6 AN: 12

South Asian (SAS) AF: 0.750 AC: 6 AN: 8

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.478 AC: 86 AN: 180

Other (OTH) AF: 0.500 AC: 5 AN: 10

GnomAD4 genome AF: 0.418 AC: 63473 AN: 152024 Hom.: 14200 Cov.: 32 AF XY: 0.411 AC XY: 30549 AN XY: 74286

African (AFR) AF: 0.277 AC: 11487 AN: 41458

American (AMR) AF: 0.389 AC: 5939 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.489 AC: 1696 AN: 3470

East Asian (EAS) AF: 0.381 AC: 1976 AN: 5188

South Asian (SAS) AF: 0.417 AC: 2010 AN: 4818

European-Finnish (FIN) AF: 0.398 AC: 4192 AN: 10536

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.509 AC: 34602 AN: 67978

Other (OTH) AF: 0.425 AC: 895 AN: 2108

Alfa AF: 0.458 Hom.: 2048

Bravo AF: 0.408

Asia WGS AF: 0.445 AC: 1545 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Immunodeficiency due to CD25 deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.78
DANN	Benign	0.67
PhyloP100		-0.62
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: rs1570538; hg19: chr10-6053568;