X-71110633-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS2BS1

This summary comes from the ClinGen Evidence Repository: The NM_000206.3(IL2RG):c.325G>A (p.Glu109Lys) 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 an intermediate allele frequency, with a popmax filtering allele frequency in gnomAD v2.1.1 of 0.0006719 (based on 74/92629 alleles in the non-Finnish European population) which is below the SCID VCEP established threshold of >0.00249 for BS1 and above the PM2 threshold of <0.000124. However, the highest MAF is in the Finnish population at 0.004561 (85/18638 alleles, 28 hemizygotes and 1 homozygote) which is above the SCID VCEP established threshold of >0.00249. As this population is not known to have a higher prevalence of this is considered to meet BS1. Sixty-two adult hemizygous males with this variant are present in the gnomADv2.1.1 dataset as well as a homozygous female (BS2). In summary, this variant is classified as Benign. Criteria applied: BS1, BS2 (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10443889/MONDO:0010315/129

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., 25 hem., cov: 22)

Exomes 𝑓: 0.00076 ( 1 hom. 273 hem. )

Consequence

IL2RG
NM_000206.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:7

Conservation

PhyloP100: 0.249

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 Benign. Variant got -8 ACMG points.

BS1

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

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.325G>A	p.Glu109Lys	missense_variant	Exon 3 of 8	ENST00000374202.7	NP_000197.1	P31785-1
IL2RG	XM_047442089.1 link	c.325G>A	p.Glu109Lys	missense_variant	Exon 3 of 7		XP_047298045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL2RG	ENST00000374202.7 link	c.325G>A	p.Glu109Lys	missense_variant	Exon 3 of 8	1	NM_000206.3	ENSP00000363318.3		P31785-1
ENSG00000285171	ENST00000646505.1 link	n.325G>A		non_coding_transcript_exon_variant	Exon 3 of 12			ENSP00000496673.1		A0A2R8YE73

Frequencies

GnomAD3 genomes

AF:

0.000600

AC:

AN:

111633

Hom.:

Cov.:

AF XY:

0.000739

AC XY:

AN XY:

33815

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00114

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000737

Gnomad FIN

AF:

0.00298

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000809

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000900

AC:

165

AN:

183382

Hom.:

AF XY:

0.000796

AC XY:

AN XY:

67838

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00134

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000682

Gnomad FIN exome

AF:

0.00437

Gnomad NFE exome

AF:

0.000831

Gnomad OTH exome

AF:

0.000662

GnomAD4 exome

AF:

0.000762

AC:

835

AN:

1095797

Hom.:

Cov.:

AF XY:

0.000756

AC XY:

273

AN XY:

361195

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00103

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000702

Gnomad4 FIN exome

AF:

0.00412

Gnomad4 NFE exome

AF:

0.000697

Gnomad4 OTH exome

AF:

0.000434

GnomAD4 genome

AF:

0.000600

AC:

AN:

111686

Hom.:

Cov.:

AF XY:

0.000738

AC XY:

AN XY:

33878

show subpopulations

Gnomad4 AFR

AF:

0.0000325

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00114

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000740

Gnomad4 FIN

AF:

0.00298

Gnomad4 NFE

AF:

0.000809

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000809

Hom.:

Bravo

AF:

0.000450

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000892

AC:

ExAC

AF:

0.00101

AC:

122

EpiCase

AF:

0.000382

EpiControl

AF:

0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

X-linked severe combined immunodeficiency

Benign:4

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dec 09, 2019

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 14, 2023

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000206.3(IL2RG):c.325G>A (p.Glu109Lys) 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 an intermediate allele frequency, with a popmax filtering allele frequency in gnomAD v2.1.1 of 0.0006719 (based on 74/92629 alleles in the non-Finnish European population) which is below the SCID VCEP established threshold of >0.00249 for BS1 and above the PM2 threshold of <0.000124. However, the highest MAF is in the Finnish population at 0.004561 (85/18638 alleles, 28 hemizygotes and 1 homozygote) which is above the SCID VCEP established threshold of >0.00249. As this population is not known to have a higher prevalence of this is considered to meet BS1. Sixty-two adult hemizygous males with this variant are present in the gnomADv2.1.1 dataset as well as a homozygous female (BS2). In summary, this variant is classified as Benign. Criteria applied: BS1, BS2 (VCEP specifications version 1). -

not specified

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 08, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.62

DEOGEN2

Uncertain

0.53

D;.;T

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.70

T;T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.0052

T;T;T

MetaSVM

Benign

-0.48

MutationAssessor

Benign

1.1

L;.;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.080

N;N;N

REVEL

Benign

0.28

Sift

Benign

0.94

T;T;T

Sift4G

Benign

0.76

T;.;.

Polyphen

0.0

B;.;.

Vest4

0.066

MVP

0.79

MPC

0.66

ClinPred

0.011

GERP RS

1.5

Varity_R

0.14

gMVP

0.86

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