X-71111440-C-A

Position:

• chrX-71111440-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2_Supporting PVS1

This summary comes from the ClinGen Evidence Repository: The c.100G>T (p.Glu34Ter) (NM_000206.3) variant in IL2RG is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 1/8 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).The variant is absent in gnomAD v4 (PM2_supporting). There are no publications for this variant in the literature. In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1_Met, PM2_supporting (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA413497595/MONDO:0010315/129

• Frequency: Genomes: not found (cov: 22)
• Consequence: IL2RG NM_000206.3 stop_gained
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 1.91

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 9 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL2RG	NM_000206.3	c.100G>T	p.Glu34*	stop_gained	1/8	ENST00000374202.7	NP_000197.1
IL2RG	XM_047442089.1	c.100G>T	p.Glu34*	stop_gained	1/7		XP_047298045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL2RG	ENST00000374202.7	c.100G>T	p.Glu34*	stop_gained	1/8	1	NM_000206.3	ENSP00000363318.3
ENSG00000285171	ENST00000646505.1	n.100G>T		non_coding_transcript_exon_variant	1/12			ENSP00000496673.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

X-linked severe combined immunodeficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 26, 2017	For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in IL2RG are known to be pathogenic (PMID: 9058718, 10794430). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu34*) in the IL2RG gene. It is expected to result in an absent or disrupted protein product. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jun 14, 2024	The c.100G>T (p.Glu34Ter) (NM_000206.3) variant in IL2RG is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 1/8 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).The variant is absent in gnomAD v4 (PM2_supporting). There are no publications for this variant in the literature. In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1_Met, PM2_supporting (VCEP specifications version 1). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	38
DANN	Uncertain	0.99
FATHMM_MKL	Benign	0.68	D
Vest4		0.84
ClinPred		0.99	D
GERP RS		3.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1556331272; hg19: chrX-70331290; COSMIC: COSV52147730; COSMIC: COSV52147730;