rs193922348

Variant names:

• chrX-71110295-A-C
• rs193922348
• NM_000206.3:c.455T>G

Your query was ambiguous. Multiple possible variants found:

• chrX-71110295-A-C
• chrX-71110295-A-G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000206.3(IL2RG):​c.455T>G​(p.Val152Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V152A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: IL2RG NM_000206.3 missense, splice_region
• Scores: Splicing: ADA: 0.5144
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.25
• Publications: 6 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 11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 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-71110295-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 36386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant X-71110295-A-C is Pathogenic according to our data. Variant chrX-71110295-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 624584.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RG	NM_000206.3	c.455T>G	p.Val152Gly	missense_variant, splice_region_variant	Exon 4 of 8	ENST00000374202.7	NP_000197.1
IL2RG	NM_001438870.1	c.455T>G	p.Val152Gly	missense_variant, splice_region_variant	Exon 4 of 7		NP_001425799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL2RG	ENST00000374202.7	c.455T>G	p.Val152Gly	missense_variant, splice_region_variant	Exon 4 of 8	1	NM_000206.3	ENSP00000363318.3
ENSG00000285171	ENST00000646505.1	n.455T>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 12			ENSP00000496673.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

X-linked severe combined immunodeficiency Pathogenic:1

Feb 28, 2019

Laboratory of Pediatric Immunoinfectivology, Tor Vergata University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

SCID (Severe Combined Immunodeficiency) T-, B+, NK+, reduced IgM and IgA -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.71
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.61	T;T
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M;.
PhyloP100		5.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.60
MutPred		0.83		Loss of stability (P = 0.0156);.;
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.3
PromoterAI		-0.011	Neutral
Varity_R		0.99
gMVP		0.98
Mutation Taster		=29/71	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.51
dbscSNV1_RF	Benign	0.62
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: rs193922348; hg19: chrX-70330145;