rs1556330234

chrX-71109265-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000206.3(IL2RG):c.720G>A(p.Trp240Ter) variant causes a stop gained 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: IL2RG NM_000206.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-71109265-C-T is Pathogenic according to our data. Variant chrX-71109265-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 463384.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL2RG	NM_000206.3	c.720G>A	p.Trp240Ter	stop_gained	5/8	ENST00000374202.7
IL2RG	XM_047442089.1	c.720G>A	p.Trp240Ter	stop_gained	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL2RG	ENST00000374202.7	c.720G>A	p.Trp240Ter	stop_gained	5/8	1	NM_000206.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked severe combined immunodeficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

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
MutationTaster	Benign	1.0	A;A;N
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;