chrX-71107741-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received -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

Publications

0 publications found

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 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

IL2RG links:

ENSG00000285171 (HGNC:):

ENSG00000285171 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received -1 ACMG points.

BS2

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RG	NM_000206.3 link	c.1105A>G	p.Thr369Ala	missense_variant	Exon 8 of 8	ENST00000374202.7	NP_000197.1	P31785-1
IL2RG	NM_001438870.1 link	c.*225A>G		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 link	c.1105A>G	p.Thr369Ala	missense_variant	Exon 8 of 8	1	NM_000206.3	ENSP00000363318.3		P31785-1
ENSG00000285171	ENST00000646505.1 link	n.924+536A>G		intron_variant	Intron 7 of 11			ENSP00000496673.1		A0A2R8YE73

Frequencies

GnomAD3 genomes

AF:

0.0000536

AC:

AN:

111905

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000323

AC:

AN:

123703

AF XY:

0.0000515

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 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

African (AFR)

AF:

0.00

AC:

AN:

23579

American (AMR)

AF:

0.00

AC:

AN:

22035

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14743

East Asian (EAS)

AF:

0.00

AC:

AN:

29082

South Asian (SAS)

AF:

0.00

AC:

AN:

41832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37657

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3707

European-Non Finnish (NFE)

AF:

0.0000635

AC:

AN:

803571

Other (OTH)

AF:

0.00

AC:

AN:

42496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000536

AC:

AN:

111905

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34103

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30719

American (AMR)

AF:

0.00

AC:

AN:

10677

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3536

South Asian (SAS)

AF:

0.00

AC:

AN:

2697

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6139

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.000113

AC:

AN:

53061

Other (OTH)

AF:

0.00

AC:

AN:

1507

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

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

Mar 11, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 14, 2023

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

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). -

Oct 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

IL2RG-related disorder

Benign:1

Sep 17, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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;.;.

PhyloP100

0.54

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

Mutation Taster

=94/6

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chrX-71107741-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over