X-71109321-G-C

Variant names:

• chrX-71109321-G-C
• NM_000206.3:c.664C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_000206.3(IL2RG):​c.664C>G​(p.Arg222Gly) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: IL2RG NM_000206.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.47

Genes affected

IL2RG (HGNC:6010): (interleukin 2 receptor subunit gamma) The protein encoded by this gene is an important signaling component of many interleukin receptors, including those of interleukin -2, -4, -7 and -21, and is thus referred to as the common gamma chain. Mutations in this gene cause X-linked severe combined immunodeficiency (XSCID), as well as X-linked combined immunodeficiency (XCID), a less severe immunodeficiency disorder. [provided by RefSeq, Mar 2010]

ENSG00000285171 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain Fibronectin type-III (size 97) in uniprot entity IL2RG_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000206.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884
• PP5: Variant X-71109321-G-C is Pathogenic according to our data. Variant chrX-71109321-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2773232.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RG	NM_000206.3	c.664C>G	p.Arg222Gly	missense_variant	Exon 5 of 8	ENST00000374202.7	NP_000197.1
IL2RG	XM_047442089.1	c.664C>G	p.Arg222Gly	missense_variant	Exon 5 of 7		XP_047298045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL2RG	ENST00000374202.7	c.664C>G	p.Arg222Gly	missense_variant	Exon 5 of 8	1	NM_000206.3	ENSP00000363318.3
ENSG00000285171	ENST00000646505.1	n.664C>G		non_coding_transcript_exon_variant	Exon 5 of 12			ENSP00000496673.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked severe combined immunodeficiency Pathogenic:1

Jan 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 222 of the IL2RG protein (p.Arg222Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with severe combined immunodeficiency (Invitae). 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 expected to disrupt IL2RG protein function with a positive predictive value of 80%. This variant disrupts the p.Arg222 amino acid residue in IL2RG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7557965, 9399950, 10794431, 16227049, 25042067, 29948574, 31965297). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;.
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.5	M;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Pathogenic	0.77
Sift	Benign	0.031	D;D;T
Sift4G	Uncertain	0.036	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.72
MutPred		0.72		Loss of MoRF binding (P = 0.0101);.;.;
MVP		1.0
MPC		1.7
ClinPred		0.98	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.74
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-70329171;