rs1556330234

Positions:

• chrX-71109265-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2_Supporting PVS1 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.720G>A (p.Trp240Ter) (NM_000206.3) variant in IL2RG is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 5/8, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 Met).This variant is absent from gnomAD v4 (PM2_Supporting). At least one proband in the literature presents: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5 pts) + XY male sex (0.5 pts) + SCID phenotype corrected by IL2RG gene therapy WITHOUT CNV testing reported (1 pt). Total is 2 points, PP4_Moderate.In summary, this variant meets the criteria to be classified as Pathogenic for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, and PP4_Moderate (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA413495887/MONDO:0010315/129

• Frequency: Genomes: not found (cov: 23)
• Consequence: IL2RG NM_000206.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 4.30

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL2RG	NM_000206.3	c.720G>A	p.Trp240*	stop_gained	5/8	ENST00000374202.7	NP_000197.1
IL2RG	XM_047442089.1	c.720G>A	p.Trp240*	stop_gained	5/7		XP_047298045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL2RG	ENST00000374202.7	c.720G>A	p.Trp240*	stop_gained	5/8	1	NM_000206.3	ENSP00000363318.3
ENSG00000285171	ENST00000646505.1	n.720G>A		non_coding_transcript_exon_variant	5/12			ENSP00000496673.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

X-linked severe combined immunodeficiency Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jun 13, 2024	The c.720G>A (p.Trp240Ter) (NM_000206.3) variant in IL2RG is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 5/8, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 Met). This variant is absent from gnomAD v4 (PM2_Supporting). At least one proband in the literature presents: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5 pts) + XY male sex (0.5 pts) + SCID phenotype corrected by IL2RG gene therapy WITHOUT CNV testing reported (1 pt). Total is 2 points, PP4_Moderate. In summary, this variant meets the criteria to be classified as Pathogenic for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, and PP4_Moderate (VCEP specifications version 1). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 01, 2016	A different variant, c.719G>A, which results in the same truncating effect (p.Trp240*) on the protein and absent IL2RG expression, has been observed in a patient affected with classic X-linked SCID (IL2RGbase, http://research.nhgri.nih.gov/scid/IL2RGbase.shtml). In addition, fourteen unrelated patients with classic X-linked SCID have been observed in IL2RGbase with truncating mutations in exon 5 showing nonsense-mediated decay and absence of IL2RG mRNA (Personal communication, Dr. Jennifer Puck). For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, truncating variants in IL2RG are known to be pathogenic (PMID: 9058718, 10794430). This sequence change creates a premature translational stop signal at codon 240 (p.Trp240*) of the IL2RG gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.49	T
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.98	T
PROVEAN	Benign	-0.16	N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.24		Gain of ubiquitination at E2 (P = 0.0082);
MVP		0.94
ClinPred		0.99	D
GERP RS		4.7

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: rs1556330234; hg19: chrX-70329115;