X-71110614-C-T

Variant names:

• chrX-71110614-C-T
• rs1556330755
• NM_000206.3:c.344G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 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. C115R) has been classified as 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
• Publications: 0 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 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 3 uncertain in NM_000206.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-71110615-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 10025.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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 VariationId is 463381.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RG	NM_000206.3	c.344G>A	p.Cys115Tyr	missense_variant	Exon 3 of 8	ENST00000374202.7	NP_000197.1
IL2RG	NM_001438870.1	c.344G>A	p.Cys115Tyr	missense_variant	Exon 3 of 7		NP_001425799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL2RG	ENST00000374202.7	c.344G>A	p.Cys115Tyr	missense_variant	Exon 3 of 8	1	NM_000206.3	ENSP00000363318.3
ENSG00000285171	ENST00000646505.1	n.344G>A		non_coding_transcript_exon_variant	Exon 3 of 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

Jul 11, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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. 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). 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). 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.

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
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;.;.
PhyloP100		4.1
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-10	D;D;D
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;.;.
Vest4		0.94
ClinPred		1.0	D
GERP RS		5.4
PromoterAI		-0.0046	Neutral
Varity_R		0.99
gMVP		1.0
Mutation Taster		=16/84	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1556330755; hg19: chrX-70330464;