rs1556329779

Positions:

• chrX-71108290-TGGTATTCA-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000206.3(IL2RG):​c.903_910del​(p.Glu302ArgfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: IL2RG NM_000206.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.55

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-71108290-TGGTATTCA-T is Pathogenic according to our data. Variant chrX-71108290-TGGTATTCA-T is described in ClinVar as [Pathogenic]. Clinvar id is 463387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL2RG	NM_000206.3	c.903_910del	p.Glu302ArgfsTer11	frameshift_variant	7/8	ENST00000374202.7
IL2RG	XM_047442089.1	c.*23_*30del		3_prime_UTR_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL2RG	ENST00000374202.7	c.903_910del	p.Glu302ArgfsTer11	frameshift_variant	7/8	1	NM_000206.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked severe combined immunodeficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 04, 2017	In summary, this is a novel truncation that disrupts a protein domain that is essential for proper IL2 receptor function. Therefore this variant has been classified as Pathogenic. While the effect of this particular variant has not been studied, it is expected to disrupt the C-terminal region of the interleukin receptor common gamma chain, which is known to be critical for proper association with Jak3 (PMID: 7973658, 7973659). Deletions affecting this intracellular region of the protein have been shown to lead to defects in signal transduction, including loss of ability to induce c-myc, c-fos, and c-jun expression (PMID: 7683423). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an IL2RG-related disease. This sequence change deletes 8 nucleotides from exon 7 of the IL2RG mRNA (c.903_910delTGAATACC), causing a frameshift at codon 302. This creates a premature translational stop signal in the last exon of the IL2RG mRNA (p.Glu302Argfs*11). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 66 amino acids of the IL2RG protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1556329779; hg19: chrX-70328140;