rs1602287912

Variant names:

• chrX-71107752-A-G
• rs1602287912
• NM_000206.3:c.1094T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000206.3(IL2RG):​c.1094T>C​(p.Leu365Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: IL2RG NM_000206.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.883
• 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: 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22056901).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RG	NM_000206.3	c.1094T>C	p.Leu365Pro	missense_variant	Exon 8 of 8	ENST00000374202.7	NP_000197.1
IL2RG	NM_001438870.1	c.*214T>C		3_prime_UTR_variant	Exon 7 of 7		NP_001425799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL2RG	ENST00000374202.7	c.1094T>C	p.Leu365Pro	missense_variant	Exon 8 of 8	1	NM_000206.3	ENSP00000363318.3
ENSG00000285171	ENST00000646505.1	n.924+525T>C		intron_variant	Intron 7 of 11			ENSP00000496673.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1029395 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 328077

African (AFR) AF: 0.00 AC: 0 AN: 23886

American (AMR) AF: 0.00 AC: 0 AN: 23400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15149

East Asian (EAS) AF: 0.00 AC: 0 AN: 29390

South Asian (SAS) AF: 0.00 AC: 0 AN: 43821

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38025

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3788

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 808947

Other (OTH) AF: 0.00 AC: 0 AN: 42989

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked severe combined immunodeficiency Uncertain:1

Sep 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine with proline at codon 365 of the IL2RG protein (p.Leu365Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with IL2RG-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	12
DANN	Benign	0.53
DEOGEN2	Uncertain	0.50	T;.;.
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.56	T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Uncertain	0.55	D
MutationAssessor	Uncertain	2.3	M;.;.
PhyloP100		0.88
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.43	N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.057	T;T;T
Sift4G	Benign	0.12	T;D;T
Polyphen		1.0	D;B;.
Vest4		0.30
MutPred		0.32		Loss of stability (P = 0.0088);.;.;
MVP		0.85
MPC		1.1
ClinPred		0.28	T
GERP RS		3.2
Varity_R		0.12
gMVP		0.52
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1602287912; hg19: chrX-70327602;