rs1057520644

chrX-71110964-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000206.3(IL2RG):c.202G>A(p.Glu68Lys) variant causes a missense change. 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E68G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 21)
• Consequence: IL2RG NM_000206.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 4.15

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a disulfide_bond (size 10) in uniprot entity IL2RG_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000206.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant X-71110964-C-T is Pathogenic according to our data. Variant chrX-71110964-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 379561.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL2RG	NM_000206.3	c.202G>A	p.Glu68Lys	missense_variant	2/8	ENST00000374202.7
IL2RG	XM_047442089.1	c.202G>A	p.Glu68Lys	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL2RG	ENST00000374202.7	c.202G>A	p.Glu68Lys	missense_variant	2/8	1	NM_000206.3	P1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

X-linked severe combined immunodeficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 13, 2022	Experimental studies have shown that this missense change affects IL2RG function (PMID: 8088810). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 379561). This variant is also known as 216G>A E68K. This missense change has been observed in individuals with X-linked severe combined immunodeficiency (X-SCID) and an individual affected with both West syndrome (WS) and X-SCID (PMID: 8088810, 11129345, 24534054). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 68 of the IL2RG protein (p.Glu68Lys). -
Pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jan 31, 2024	NM_000206.3(IL2RG):c.202G>A is a missense variant predicted to cause substitution of Glutamic Acid by Lysine at amino acid 68 (p.Glu68Lys). The variant is absent in gnomAD v4 (PM2_supporting). Male patient (0.5 pt.) with SCID (0.5 pt.), genome sequencing conducted (1 pt.), Absent CD132 expression (1 pt.), T-B+NK- lymphocyte subset profile (0.5 pt.); total :3.5 pts PMID: 30778343 (PP4_moderate). This variant is found in multiple unrelated affected probands (total pts. >16) (PS4_very strong) (PMIDs: 9058718, 24534054,11129345, 32477911,31456805, 27484032,31031743,30778343). As per the SCID VCEP specifications and the Bayesian interpretation of the ACMG/AMP combining rules, 1 Very Strong,1 Moderate and 1 Supporting criteria results in a Pathogenic classification. In summary, this variant meets the criteria to be classified as Pathogenic for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_supporting,PP4_moderate,PS4_very strong (VCEP specifications version 1). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 15, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2021	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31456805, 28747913, 24534054, 22105576, 8088810, 9058718, 11129345, 30778343, 31031743, 27484032, 10993286, 32477911) -

Combined immunodeficiency, X-linked Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D;.;D
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.2	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.4	N;N;D
REVEL	Pathogenic	0.79
Sift	Benign	0.14	T;T;D
Sift4G	Pathogenic	0.0	D;.;.
Polyphen		0.99	D;.;.
Vest4		0.55
MutPred		0.93		Gain of methylation at E68 (P = 0.0044);.;.;
MVP		1.0
MPC		1.4
ClinPred		0.94	D
GERP RS		5.4
Varity_R		0.69
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: rs1057520644; hg19: chrX-70330814;