X-71108323-A-T

Position:

• chrX-71108323-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The ENST00000374202.7(IL2RG):​c.878T>A​(p.Leu293Gln) 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 (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: IL2RG ENST00000374202.7 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.88

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant X-71108323-A-T is Pathogenic according to our data. Variant chrX-71108323-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 10023.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL2RG	NM_000206.3	c.878T>A	p.Leu293Gln	missense_variant	7/8	ENST00000374202.7	NP_000197.1
IL2RG	XM_047442089.1	c.781T>A	p.Ter261ArgextTer3	stop_lost	6/7		XP_047298045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL2RG	ENST00000374202.7	c.878T>A	p.Leu293Gln	missense_variant	7/8	1	NM_000206.3	ENSP00000363318	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Combined immunodeficiency, X-linked Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1995

- -

X-linked severe combined immunodeficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 05, 2023

This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 293 of the IL2RG protein (p.Leu293Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with X-linked combined immunodeficiency (XCID) (PMID: 7883965, 12126929). It has also been observed to segregate with disease in related individuals. This variant is also known as Leu271Gln. ClinVar contains an entry for this variant (Variation ID: 10023). 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%. Experimental studies have shown that this missense change affects IL2RG function (PMID: 7973658). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Uncertain	0.42	T;.;.
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.85	D;T;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.2	M;.;.
MutationTaster	Benign	0.00041	A;A;A
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.64	N;D;N
REVEL	Pathogenic	0.65
Sift	Benign	0.061	T;D;T
Sift4G	Uncertain	0.017	D;D;D
Polyphen		0.93	P;P;.
Vest4		0.73
MutPred		0.76		Gain of disorder (P = 0.0134);.;.;
MVP		1.0
MPC		1.4
ClinPred		0.85	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.74

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: rs137852510; hg19: chrX-70328173;