X-71110295-A-G

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000206.3(IL2RG):​c.455T>C​(p.Val152Ala) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V152G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: IL2RG NM_000206.3 missense, splice_region
• Scores: Splicing: ADA: 0.2496
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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 18 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-C is described in ClinVar as Pathogenic. ClinVar VariationId is 624584.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant X-71110295-A-G is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RG	NM_000206.3	c.455T>C	p.Val152Ala	missense_variant, splice_region_variant	Exon 4 of 8	ENST00000374202.7	NP_000197.1
IL2RG	NM_001438870.1	c.455T>C	p.Val152Ala	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>C	p.Val152Ala	missense_variant, splice_region_variant	Exon 4 of 8	1	NM_000206.3	ENSP00000363318.3
ENSG00000285171	ENST00000646505.1	n.455T>C		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

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked severe combined immunodeficiency Pathogenic:3

Aug 27, 2013

UCLA Clinical Genomics Center, UCLA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

Aug 11, 2017

Immunology Clinic, Ucla

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.70
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.71	T;T
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M;.
PhyloP100		5.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0040	D;D
Sift4G	Pathogenic	0.0	D;.
Vest4		0.70
ClinPred		0.98	D
GERP RS		5.3
PromoterAI		0.0023	Neutral
Varity_R		0.93
gMVP		0.93
Mutation Taster		=39/61	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.25
dbscSNV1_RF	Benign	0.47
SpliceAI score (max)		0.070		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;