X-71109309-G-A

Variant names:

• chrX-71109309-G-A
• rs869320659
• NM_000206.3:c.676C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1_Strong PS3_Supporting PP4 PM2_Supporting PM6 PS4

This summary comes from the ClinGen Evidence Repository: The NM_000206.3(IL2RG):c.676C>T (p.Arg226Cys) missense variant resides within a CpG dinucleotide region, cDNA 676-677 encoding amino acid R226, of IL2RG that is defined as a mutational hotspot (PMID:7668284; PM1_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The male (0.5pt) patient of PMID:14966353 has a T-B+NK- lymphocyte subset profile (0.5pt) [CD3: 2.5%; CD19: 95.4%; CD16/CD56: 0.5%] which is specific for SCID due to gamma chain deficiency (1pt; PP4). In a second case, the R226C variant arose de novo as a somatic mutation early in embryogenesis in the mother of the patient, 1 pt, PM6_Moderate (PMID:23683512).At least eight additional male X-SCID patients have been reported (PMIDs: 9058718, 11129345, 22936741, 7668284) with this hemizygous variant (total 4.5pt; PS4). PMID:7632950 Examined the mutant 7 chain distribution by confocal microscopy in transiently transfected COS-7 cells, comparing it with the wild-type 7 chain distribution. The mutant 7 chain could not be detected by an antihuman IL-2 receptor 7 chain monoclonal antibody, TUGh4, on the cell surface of the transfected COS-7 cells. This result was in sharp contrast to that obtained with the wild-type γ chain, which was clearly stained by TUGh4 on the transfected cells. PS3_Supporting is met.In summary, this variant meets the criteria to be classified as Pathogenic for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PS4, PM1_Strong, PM6_Moderate, PM2_Supporting, PS3_Supporting, and PP4. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA358784/MONDO:0010315/129

• Frequency: Genomes: not found (cov: 23)
• Consequence: IL2RG NM_000206.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 3.56
• Publications: 17 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 13 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000206.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RG	NM_000206.3	MANE Select	c.676C>T	p.Arg226Cys	missense	Exon 5 of 8	NP_000197.1
	IL2RG	NM_001438870.1		c.676C>T	p.Arg226Cys	missense	Exon 5 of 7	NP_001425799.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RG	ENST00000374202.7	TSL:1 MANE Select	c.676C>T	p.Arg226Cys	missense	Exon 5 of 8	ENSP00000363318.3
	ENSG00000285171	ENST00000646505.1		n.676C>T		non_coding_transcript_exon	Exon 5 of 12	ENSP00000496673.1
	IL2RG	ENST00000482750.6	TSL:5	c.676C>T	p.Arg226Cys	missense	Exon 5 of 7	ENSP00000421262.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	X-linked severe combined immunodeficiency (6)
2	-	-	X-linked severe combined immunodeficiency;CN030319:Combined immunodeficiency, X-linked (2)
1	-	-	Combined immunodeficiency, X-linked (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.64
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.91		Loss of MoRF binding (P = 0.0065)
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.87
Mutation Taster		=12/88	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: rs869320659; hg19: chrX-70329159;