NM_000417.3:c.193A>G

Variant names:

• chr10-6025897-T-C
• rs372359952
• NM_000417.3:c.193A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000417.3(IL2RA):​c.193A>G​(p.Met65Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: IL2RA NM_000417.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.07

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]

ENSG00000229664 (HGNC:58167):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14042988).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RA	NM_000417.3	c.193A>G	p.Met65Val	missense_variant	Exon 2 of 8	ENST00000379959.8	NP_000408.1
IL2RA	NM_001308242.2	c.193A>G	p.Met65Val	missense_variant	Exon 2 of 7		NP_001295171.1
IL2RA	NM_001308243.2	c.193A>G	p.Met65Val	missense_variant	Exon 2 of 6		NP_001295172.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL2RA	ENST00000379959.8	c.193A>G	p.Met65Val	missense_variant	Exon 2 of 8	1	NM_000417.3	ENSP00000369293.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Mar 31, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.193A>G (p.M65V) alteration is located in exon 2 (coding exon 2) of the IL2RA gene. This alteration results from a A to G substitution at nucleotide position 193, causing the methionine (M) at amino acid position 65 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Immunodeficiency due to CD25 deficiency Uncertain:1

Mar 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 65 of the IL2RA protein (p.Met65Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IL2RA-related conditions. ClinVar contains an entry for this variant (Variation ID: 534229). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt IL2RA protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	6.7
DANN	Benign	0.72
DEOGEN2	Uncertain	0.53	D;.;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.60	T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.073
Sift	Benign	0.098	T;D;T
Sift4G	Benign	0.10	T;T;T
Polyphen		0.010	B;B;.
Vest4		0.22
MutPred		0.63		Loss of disorder (P = 0.0453);Loss of disorder (P = 0.0453);Loss of disorder (P = 0.0453);
MVP		0.47
MPC		0.20
ClinPred		0.14	T
GERP RS		2.0
Varity_R		0.19
gMVP		0.35

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: rs372359952; hg19: chr10-6067860;