X-71109321-G-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP5_Moderate

The NM_000206.3(IL2RG):​c.664C>A​(p.Arg222Ser) 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 7 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, 0.835
• PP5: Variant X-71109321-G-T is Pathogenic according to our data. Variant chrX-71109321-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2504922.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>A	p.Arg222Ser	missense_variant	Exon 5 of 8	ENST00000374202.7	NP_000197.1
IL2RG	XM_047442089.1	c.664C>A	p.Arg222Ser	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>A	p.Arg222Ser	missense_variant	Exon 5 of 8	1	NM_000206.3	ENSP00000363318.3
ENSG00000285171	ENST00000646505.1	n.664C>A		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

not provided Pathogenic:1

Jun 11, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9399950, 9058718, 33712943, 15687233) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;.;.
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.5	M;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.8	D;N;D
REVEL	Pathogenic	0.74
Sift	Benign	0.036	D;D;T
Sift4G	Uncertain	0.032	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.64
MutPred		0.70		Loss of MoRF binding (P = 0.0158);.;.;
MVP		1.0
MPC		1.6
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		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-70329171;