X-71110614-C-T

Position:

• chrX-71110614-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_000206.3(IL2RG):​c.344G>A​(p.Cys115Tyr) variant causes a missense 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C115F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: IL2RG NM_000206.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.09

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant X-71110614-C-T is Pathogenic according to our data. Variant chrX-71110614-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 463381.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL2RG	NM_000206.3	c.344G>A	p.Cys115Tyr	missense_variant	3/8	ENST00000374202.7	NP_000197.1
IL2RG	XM_047442089.1	c.344G>A	p.Cys115Tyr	missense_variant	3/7		XP_047298045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL2RG	ENST00000374202.7	c.344G>A	p.Cys115Tyr	missense_variant	3/8	1	NM_000206.3	ENSP00000363318.3
ENSG00000285171	ENST00000646505.1	n.344G>A		non_coding_transcript_exon_variant	3/12			ENSP00000496673.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked severe combined immunodeficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 11, 2016

A B-lymphoblastoid cell line generated from patient blood cells showed a reduction in their affinity for IL-2 compared with WT, suggesting that p.Cys115Tyr has a profound impact on protein function (PMID: 8299698). In summary, this is a rare missense variant that is absent from the general population, has been found in an affected individual that showed a decrease in the IL2 receptor function and alters a cysteine residue that is probably important for protein structure. Although all the evidence recorded indicates that this variant is deleterious, in the absence of segregation data it has been classified as Likely Pathogenic. The cysteine replaced is conserved in all of the members of the cytokine I receptor family and is thought to provide strong spatial constraints for tertiary folding through disulfide bonding (PMID: 2169613, 9058718). In addition, variants within exons 2,3 of the IL2RG gene that substitute or generate cysteine residues are overrepresented among patients with SCID (PMID: 8961626). This variant has been reported in an individual affected with severe combined immunodeficiency (SCID) (PMID: 8299698). This variant has also been observed in an individual with T-B+NK- SCID, a finding that is highly specific for IL2RG-related SCID (Invitae). This variant is also known as Cys93Tyr in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 115 of the IL2RG protein (p.Cys115Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;D
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.2	M;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-10	D;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;.;.
Polyphen		1.0	D;.;.
Vest4		0.94
MutPred		0.73		Loss of sheet (P = 0.0357);.;.;
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.99
gMVP		1.0

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: rs1556330755; hg19: chrX-70330464;