X-71107741-T-C

Position:

chrX-71107741-T-C

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000206.3(IL2RG):c.1105A>G (p.Thr369Ala) 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. It occurs at a low allele frequency in gnomAD v2.1. of 0.00002258 which is below the SCID VCEP established threshold of <0.000124, however this includes two adult hemizygotes (PM2_NotMet, BS2_Supporting). In summary, this variant is classified as uncertain significance due to insufficient information. Criteria applied: BS2_supporting (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10443749/MONDO:0010315/129

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000050 ( 0 hom. 15 hem. )

Consequence

IL2RG
NM_000206.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2B:2

Conservation

PhyloP100: 0.539

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 -1 ACMG points.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL2RG	NM_000206.3 linkuse as main transcript	c.1105A>G	p.Thr369Ala	missense_variant	8/8	ENST00000374202.7	NP_000197.1
IL2RG	XM_047442089.1 linkuse as main transcript	c.*225A>G		3_prime_UTR_variant	7/7		XP_047298045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL2RG	ENST00000374202.7 linkuse as main transcript	c.1105A>G	p.Thr369Ala	missense_variant	8/8	1	NM_000206.3	ENSP00000363318	P1	P31785-1

Frequencies

GnomAD3 genomes

AF:

0.0000536

AC:

AN:

111905

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34103

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:

0.000113

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000323

AC:

AN:

123703

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

38807

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:

0.0000668

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000501

AC:

AN:

1018702

Hom.:

Cov.:

AF XY:

0.0000466

AC XY:

AN XY:

322066

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:

0.0000635

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000536

AC:

AN:

111905

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34103

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:

0.000113

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000167

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

X-linked severe combined immunodeficiency

Uncertain:2Benign:1

Uncertain significance, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Nov 14, 2023	NM_000206.3(IL2RG):c.1105A>G (p.Thr369Ala) 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. It occurs at a low allele frequency in gnomAD v2.1. of 0.00002258 which is below the SCID VCEP established threshold of <0.000124, however this includes two adult hemizygotes (PM2_NotMet, BS2_Supporting). In summary, this variant is classified as uncertain significance due to insufficient information. Criteria applied: BS2_supporting (VCEP specifications version 1). -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 11, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

IL2RG-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.72

DEOGEN2

Benign

0.38

T;.;.

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.67

T;T;T

M_CAP

Benign

0.081

MetaRNN

Benign

0.075

T;T;T

MetaSVM

Uncertain

0.031

MutationAssessor

Benign

1.8

L;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.44

N;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.17

T;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.0

B;B;.

Vest4

0.091

MVP

0.47

MPC

0.57

ClinPred

0.044

GERP RS

-3.0

Varity_R

0.028

gMVP

0.24

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