rs869320658

Variant names:

• chrX-71109315-G-A
• rs869320658
• NM_000206.3:c.670C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1_Strong PS3_Supporting PP4 PM2_Supporting PS4

This summary comes from the ClinGen Evidence Repository: The NM_000206.3:c.670C>T variant in IL2RG is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 224 (p.Arg226Trp). The variant has been observed in at least 10 male probands with SCID (PMIDs 28747913, 21184155, 10792291, 9633906, 9058718, 9049783) (PS4). Among these probands, one proband hemizygous for this variant was diagnosed with SCID and presented a T-B+NK- lymphocyte profile (PMID 9049783) (PP4). The variant is absent from gnomAD v4.0 (PM2_Supporting). The variant affects CpG dinucleotides at c.670C, which is defined as a mutational hotspot by the ClinGen SCID VCEP (PMID 7668284) (PM1_Strong). Surface expression of the IL-2 receptor gamma chain in patient B cells showed that the variant causes decreased surface localization of the protein, indicating that this variant impacts protein function (PMID 9058718)(PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM1_Strong, PS4, PP4_Supporting, PM2_Supporting, PS3_Supporting. (VCEP specifications version 1.0) LINK:https://erepo.genome.network/evrepo/ui/classification/CA358778/MONDO:0010315/129

• Frequency: Genomes: not found (cov: 23)
• Consequence: IL2RG NM_000206.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 2.90
• Publications: 11 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: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Myriad Women’s Health
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285171 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 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.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RG	NM_000206.3	MANE Select	c.670C>T	p.Arg224Trp	missense	Exon 5 of 8	NP_000197.1	P31785-1
	IL2RG	NM_001438870.1		c.670C>T	p.Arg224Trp	missense	Exon 5 of 7	NP_001425799.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RG	ENST00000374202.7	TSL:1 MANE Select	c.670C>T	p.Arg224Trp	missense	Exon 5 of 8	ENSP00000363318.3	P31785-1
	ENSG00000285171	ENST00000646505.1		n.670C>T		non_coding_transcript_exon	Exon 5 of 12	ENSP00000496673.1	A0A2R8YE73
	IL2RG	ENST00000482750.6	TSL:5	c.670C>T	p.Arg224Trp	missense	Exon 5 of 7	ENSP00000421262.2	H0Y8J6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	X-linked severe combined immunodeficiency (4)
2	-	-	not provided (2)
1	-	-	Combined immunodeficiency, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.9
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.92		Loss of methylation at R226 (P = 0.0235)
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.95
gMVP		0.97
Mutation Taster		=32/68	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: rs869320658; hg19: chrX-70329165; COSMIC: COSV52148736; COSMIC: COSV52148736;