rs370677485

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000206.3(IL2RG):c.821T>C(p.Ile274Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00001 in 1,195,873 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★★). Synonymous variant affecting the same amino acid position (i.e. I274I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000083 ( 0 hom. 6 hem. )

Consequence

IL2RG
NM_000206.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:7

Conservation

PhyloP100: 4.18

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL2RG	NM_000206.3 linkuse as main transcript	c.821T>C	p.Ile274Thr	missense_variant	6/8	ENST00000374202.7
IL2RG	XM_047442089.1 linkuse as main transcript	c.758-286T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL2RG	ENST00000374202.7 linkuse as main transcript	c.821T>C	p.Ile274Thr	missense_variant	6/8	1	NM_000206.3	P1	P31785-1

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112507

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34663

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000563

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000122

AC:

AN:

163372

Hom.:

AF XY:

0.00

AC XY:

AN XY:

54084

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000282

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000831

AC:

AN:

1083366

Hom.:

Cov.:

AF XY:

0.0000170

AC XY:

AN XY:

353146

show subpopulations

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:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112507

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34663

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000563

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00000831

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

X-linked severe combined immunodeficiency

Uncertain:3

Uncertain significance, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Nov 14, 2023	The NM_000206.3(IL2RG):c.821T>C (p.Ile274Thr) is a missense variant that has been reported in ClinVar, without patient information, however it has not been reported in the literature to our knowledge. This variant introduces a polar residue within the transmembrane region (amino acids 263-283) of IL2RG, which is defined as a critical functional domain by the ClinGen SCID VCEP (PM1_Strong). The filtering allele frequency (the upper threshold of the 95% CI of 2/70896) of the c.821T>C variant in IL2RG is 0.000004680 for European (non- Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.000124; PM2_Supporting). In summary, this variant is classified as uncertain significance due to insufficient information. Criteria applied: PM1_strong and PM2_supporting (VCEP specifications version 1). -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 10, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 274 of the IL2RG protein (p.Ile274Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IL2RG-related conditions. ClinVar contains an entry for this variant (Variation ID: 532191). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt IL2RG 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2019	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 14, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Feb 09, 2022	PM2 -

IL2RG-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 24, 2023

The IL2RG c.821T>C variant is predicted to result in the amino acid substitution p.Ile274Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0028% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/X-70328482-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2022

The c.821T>C (p.I274T) alteration is located in exon 6 (coding exon 6) of the IL2RG gene. This alteration results from a T to C substitution at nucleotide position 821, causing the isoleucine (I) at amino acid position 274 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Uncertain

0.64

D;.

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.66

T;T

M_CAP

Pathogenic

0.35

MetaRNN

Uncertain

0.72

D;D

MetaSVM

Uncertain

0.59

MutationAssessor

Uncertain

2.5

M;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.1

N;N

REVEL

Uncertain

0.44

Sift

Uncertain

0.0040

D;T

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.65

P;.

Vest4

0.52

MVP

0.97

MPC

1.3

ClinPred

0.82

GERP RS

4.9

Varity_R

0.14

gMVP

0.87

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

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