rs111033619

Positions:

• chrX-71110980-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.186T>A (p.Cys62Ter) (NM_000206.3) variant in IL2RG is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2/8 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 Met).The variant is absent in gnomAD v4 (PM2_supporting). Male patient (0.5 pt.), Absent CD132 expression (demonstrated by RT-PCR) (1 pt.) total :1.5 pts (PP4) (PMID:8462096). In summary, this variant meets the criteria to be classified as a 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,PP4,PM2_supporting (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA254980/MONDO:0010315/129

• Frequency: Genomes: not found (cov: 22)
• Consequence: IL2RG NM_000206.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 0.383

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 10 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.186T>A	p.Cys62Ter	stop_gained	2/8	ENST00000374202.7	NP_000197.1
IL2RG	XM_047442089.1	c.186T>A	p.Cys62Ter	stop_gained	2/7		XP_047298045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL2RG	ENST00000374202.7	c.186T>A	p.Cys62Ter	stop_gained	2/8	1	NM_000206.3	ENSP00000363318	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

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	Feb 01, 2024	The c.186T>A (p.Cys62Ter) (NM_000206.3) variant in IL2RG is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2/8 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 Met).The variant is absent in gnomAD v4 (PM2_supporting). Male patient (0.5 pt.), Absent CD132 expression (demonstrated by RT-PCR) (1 pt.) total :1.5 pts (PP4) (PMID: 8462096). In summary, this variant meets the criteria to be classified as a 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,PP4,PM2_supporting (VCEP specifications version 1). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1993	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	34
DANN	Uncertain	0.99
FATHMM_MKL	Benign	0.45	N
MutationTaster	Benign	1.0	A;A
Vest4		0.84
GERP RS		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs111033619; hg19: chrX-70330830;