10-6024499-G-T

Variant names:

• chr10-6024499-G-T
• rs12722574
• NM_000417.3:c.257-145C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000417.3(IL2RA):​c.257-145C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000019 in 526,816 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: IL2RA NM_000417.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.492
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

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.257-145C>A		intron	N/A	NP_000408.1
	IL2RA	NM_001308242.2		c.257-145C>A		intron	N/A	NP_001295171.1
	IL2RA	NM_001308243.2		c.257-145C>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.257-145C>A		intron	N/A	ENSP00000369293.3
	IL2RA	ENST00000379954.5	TSL:1	c.257-145C>A		intron	N/A	ENSP00000369287.1
	IL2RA	ENST00000447847.2	TSL:1	c.257-145C>A		intron	N/A	ENSP00000402024.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000190 AC: 1 AN: 526816 Hom.: 0 AF XY: 0.00000357 AC XY: 1 AN XY: 280054

African (AFR) AF: 0.00 AC: 0 AN: 14560

American (AMR) AF: 0.00 AC: 0 AN: 29150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16452

East Asian (EAS) AF: 0.00 AC: 0 AN: 31768

South Asian (SAS) AF: 0.00 AC: 0 AN: 52722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3844

European-Non Finnish (NFE) AF: 0.00000323 AC: 1 AN: 309202

Other (OTH) AF: 0.00 AC: 0 AN: 29038

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.62
DANN	Benign	0.78
PhyloP100		-0.49

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: rs12722574; hg19: chr10-6066462;