rs111033618

Variant names:

• chrX-71109321-G-A
• rs111033618
• NM_000206.3:c.664C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-71109321-G-A
• chrX-71109321-G-C
• chrX-71109321-G-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP1_Strong PM2_Supporting PP4_Moderate PS4

This summary comes from the ClinGen Evidence Repository: The NM_000206.3(IL2RG):c.664C>T (p.Arg222Cys) missense variant has been reported in several (atypical) SCID cases, including male (0.5pt) patient P1 (PMID:29948574) in whom the variant was detected by WES (1pt) and there was a family history of SCID (first-degree male relatives from the maternal side with suspected primary immune deficiency, who were not available for this study; 0.5pt), additionally STAT5 phosphorylation after exposure to IL-2 was virtually absent in CD4 and CD8 T cells (1pt); together these are highly specific for SCID due to gamma chain deficiency (3pt; PP4_moderate). There are 5 genotype/phenotype positive individuals in the pedigree through 11 segregations of this variant (PMID:29948574); P1 plus four second cousins are all hemizygous for this variant and affected with atypical SCID and an additional great uncle was also affected but not available for genotyping (5+ segregations; PP1_Strong). At least 15 additional male X-SCID patients have been reported (PMIDs: 25042067, 16227049, 10794431, 7557965) with this hemizygous variant (total 11pt; PS4) and this variant is absent from gnomADv2.1.1 (PM2_Supporting). 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, Pp1_Strong, PP4_Moderate and PM2_supporting. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA120885/MONDO:0010315/129

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: IL2RG NM_000206.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6 O:1
• Conservation: PhyloP100: 1.47
• Publications: 26 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.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.664C>T	p.Arg222Cys	missense	Exon 5 of 8	NP_000197.1	P31785-1
	IL2RG	NM_001438870.1		c.664C>T	p.Arg222Cys	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.664C>T	p.Arg222Cys	missense	Exon 5 of 8	ENSP00000363318.3	P31785-1
	ENSG00000285171	ENST00000646505.1		n.664C>T		non_coding_transcript_exon	Exon 5 of 12	ENSP00000496673.1	A0A2R8YE73
	IL2RG	ENST00000482750.6	TSL:5	c.664C>T	p.Arg222Cys	missense	Exon 5 of 7	ENSP00000421262.2	H0Y8J6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096583 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 361961

African (AFR) AF: 0.00 AC: 0 AN: 26362

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19370

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.00 AC: 0 AN: 54113

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40529

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840621

Other (OTH) AF: 0.00 AC: 0 AN: 46052

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000396 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	X-linked severe combined immunodeficiency (5)
1	-	-	Combined immunodeficiency, X-linked (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.87		Loss of MoRF binding (P = 0.0017)
MVP		1.0
MPC		1.8
ClinPred		0.99	D
GERP RS		2.9
Varity_R		0.60
gMVP		0.86
Mutation Taster		=22/78	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: rs111033618; hg19: chrX-70329171; COSMIC: COSV105003666; COSMIC: COSV105003666;