dbSNP rs111033617: IL2RG:p.Arg285Gln (chrX-71108599-C-T) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000206.3(IL2RG):c.854G>A(p.Arg285Gln) variant causes a missense, splice region 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

IL2RG
NM_000206.3 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 3.53

Variant links:

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 links:

ENSG00000285171 (HGNC:):

ENSG00000285171 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant X-71108599-C-T is Pathogenic according to our data. Variant chrX-71108599-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10026.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 link	c.854G>A	p.Arg285Gln	missense_variant, splice_region_variant	Exon 6 of 8	ENST00000374202.7	NP_000197.1	P31785-1
IL2RG	XM_047442089.1 link	c.758-253G>A		intron_variant	Intron 5 of 6		XP_047298045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL2RG	ENST00000374202.7 link	c.854G>A	p.Arg285Gln	missense_variant, splice_region_variant	Exon 6 of 8	1	NM_000206.3	ENSP00000363318.3		P31785-1
ENSG00000285171	ENST00000646505.1 link	n.854G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 12			ENSP00000496673.1		A0A2R8YE73

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1061917

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

336183

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

X-linked severe combined immunodeficiency

Pathogenic:3

Aug 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 285 of the IL2RG mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the IL2RG protein. This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with X-linked severe combined immunodeficiency (PMID: 7557965, 9058718, 21184155, 22039266). This variant is also known as c.868G>A (p.R285Q). ClinVar contains an entry for this variant (Variation ID: 10026). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

May 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant p.R285Q in IL2RG (NM_000206.3) has been previusly reported in affected individuals (Lee PP et al; Jones AM et al). It falls at the last nucleotide of exon 6 of the IL2RG coding sequence, which is part of the consensus splice site for this exon. Splicing predictions predict a damaging effect though the same has not been proved by functional studies. The variant is submitted to ClinVar as Pathogenic. It is novel (not in any individuals) in gnomAD Exomes. The p.R285Q variant is novel (not in any individuals) in 1000 Genomes. There is a small physicochemical difference between arginine and glutamine, which is not likely to impact secondary protein structure as these residues share similar properties. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

May 30, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RNA studies from a male with this variant demonstrate aberrant splicing with skipping of exon 6 (Kanai et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32993535, 35874699, 9150740, 7557965, 10071190, 10444186, 31031743, 11129345, 33628209, 21184155) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

D;.

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.87

D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.1

N;N

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.016

D;D

Polyphen

0.99

D;.

Vest4

0.48

MutPred

0.89

Loss of sheet (P = 0.0817);.;

MVP

1.0

MPC

1.6

ClinPred

1.0

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.54

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.79

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.79

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over