rs137852510

Variant names:

• chrX-71108323-A-T
• rs137852510
• NM_000206.3:c.878T>A

Your query was ambiguous. Multiple possible variants found:

• chrX-71108323-A-T
• chrX-71108323-A-G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3 PM2 PM4 PP5_Moderate

The NM_001438870.1(IL2RG):​c.781T>A​(p.Ter261Argext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV001201745: Experimental studies have shown that this missense change affects IL2RG function (PMID:7973658).". The gene IL2RG is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 23)
• Consequence: IL2RG NM_001438870.1 stop_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.88
• Publications: 7 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

Specifications for IL2RG are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001201745: Experimental studies have shown that this missense change affects IL2RG function (PMID: 7973658).
• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_001438870.1 Downstream stopcodon found after 272 codons.
• PP5: Variant X-71108323-A-T is Pathogenic according to our data. Variant chrX-71108323-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10023.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001438870.1. 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.878T>A	p.Leu293Gln	missense	Exon 7 of 8	NP_000197.1	P31785-1
	IL2RG	NM_001438870.1		c.781T>A	p.Ter261Argext*?	stop_lost	Exon 6 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.878T>A	p.Leu293Gln	missense	Exon 7 of 8	ENSP00000363318.3	P31785-1
	ENSG00000285171	ENST00000646505.1		n.878T>A		non_coding_transcript_exon	Exon 7 of 12	ENSP00000496673.1	A0A2R8YE73
	IL2RG	ENST00000482750.6	TSL:5	c.781T>A	p.Ter261Argext*?	stop_lost	Exon 6 of 7	ENSP00000421262.2	H0Y8J6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Combined immunodeficiency, X-linked (1)
1	-	-	X-linked severe combined immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Uncertain	0.42	T
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.64	N
REVEL	Pathogenic	0.65
Sift	Benign	0.061	T
Sift4G	Uncertain	0.017	D
Polyphen		0.93	P
Vest4		0.73
MutPred		0.76		Gain of disorder (P = 0.0134)
MVP		1.0
MPC		1.4
ClinPred		0.85	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.74
Mutation Taster		=25/75	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs137852510; hg19: chrX-70328173;