chr10-6062086-ACCTG-A

Position:

• chr10-6062086-ACCTG-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000417.3(IL2RA):​c.62_64+1delCAGG​(p.Ala21del) variant causes a splice donor, disruptive inframe deletion, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IL2RA NM_000417.3 splice_donor, disruptive_inframe_deletion, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.39

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-6062086-ACCTG-A is Pathogenic according to our data. Variant chr10-6062086-ACCTG-A is described in ClinVar as [Pathogenic]. Clinvar id is 14668.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL2RA	NM_000417.3	c.62_64+1delCAGG	p.Ala21del	splice_donor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	1/8	ENST00000379959.8	NP_000408.1
IL2RA	NM_001308242.2	c.62_64+1delCAGG	p.Ala21del	splice_donor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	1/7		NP_001295171.1
IL2RA	NM_001308243.2	c.62_64+1delCAGG	p.Ala21del	splice_donor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	1/6		NP_001295172.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL2RA	ENST00000379959.8	c.62_64+1delCAGG	p.Ala21del	splice_donor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	1/8	1	NM_000417.3	ENSP00000369293.3

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Immunodeficiency due to CD25 deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1997

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.96		Position offset: 6
DS_DL_spliceai		1.0		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886041032; hg19: chr10-6104049;