rs1556330755

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-71110614-C-A
• chrX-71110614-C-T

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>T​(p.Cys115Phe) 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: 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 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, 5 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, 0.974
• PP5: Variant X-71110614-C-A is Pathogenic according to our data. Variant chrX-71110614-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1473926.Status of the report is criteria_provided_single_submitter, 1 stars.

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.344G>T	p.Cys115Phe	missense	Exon 3 of 8	NP_000197.1	P31785-1
	IL2RG	NM_001438870.1		c.344G>T	p.Cys115Phe	missense	Exon 3 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.344G>T	p.Cys115Phe	missense	Exon 3 of 8	ENSP00000363318.3	P31785-1
	ENSG00000285171	ENST00000646505.1		n.344G>T		non_coding_transcript_exon	Exon 3 of 12	ENSP00000496673.1	A0A2R8YE73
	IL2RG	ENST00000482750.6	TSL:5	c.344G>T	p.Cys115Phe	missense	Exon 3 of 7	ENSP00000421262.2	H0Y8J6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.1
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.71		Loss of sheet (P = 0.0357)
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		5.4
PromoterAI		0.0034	Neutral
Varity_R		1.0
gMVP		1.0
Mutation Taster		=13/87	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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;