rs796051888

chr10-6025968-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000417.3(IL2RA):c.122A>C(p.Tyr41Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IL2RA NM_000417.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.05

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 10-6025968-T-G is Pathogenic according to our data. Variant chr10-6025968-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 203518.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL2RA	NM_000417.3	c.122A>C	p.Tyr41Ser	missense_variant	2/8	ENST00000379959.8
IL2RA	NM_001308242.2	c.122A>C	p.Tyr41Ser	missense_variant	2/7
IL2RA	NM_001308243.2	c.122A>C	p.Tyr41Ser	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL2RA	ENST00000379959.8	c.122A>C	p.Tyr41Ser	missense_variant	2/8	1	NM_000417.3	P1
	ENST00000440436.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Feb 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.71	D;.;.
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.77	T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-8.2	D;D;D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.83
MutPred		0.81		Gain of disorder (P = 0.0037);Gain of disorder (P = 0.0037);Gain of disorder (P = 0.0037);
MVP		0.92
MPC		0.89
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.96
gMVP		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs796051888; hg19: chr10-6067931;