rs111033619

Variant names:

• chrX-71110980-A-T
• rs111033619
• NM_000206.3:c.186T>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP4 PM2_Supporting PVS1

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
• Publications: 1 publications found

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]

IL2RG Gene-Disease associations (from GenCC):

• T-B+ severe combined immunodeficiency due to gamma chain deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics, Myriad Women’s Health
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285171 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 rank	MANE	Protein	UniProt
IL2RG	NM_000206.3	c.186T>A	p.Cys62*	stop_gained	Exon 2 of 8	ENST00000374202.7	NP_000197.1
IL2RG	NM_001438870.1	c.186T>A	p.Cys62*	stop_gained	Exon 2 of 7		NP_001425799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL2RG	ENST00000374202.7	c.186T>A	p.Cys62*	stop_gained	Exon 2 of 8	1	NM_000206.3	ENSP00000363318.3
ENSG00000285171	ENST00000646505.1	n.186T>A		non_coding_transcript_exon_variant	Exon 2 of 12			ENSP00000496673.1

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

Aug 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 01, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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). -

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
PhyloP100		0.38
Vest4		0.84
GERP RS		1.8
PromoterAI		-0.023	Neutral
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs111033619; hg19: chrX-70330830;