chrX-71110633-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

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

Publications

6 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: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000206.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RG	NM_000206.3	MANE Select	c.325G>A	p.Glu109Lys	missense	Exon 3 of 8	NP_000197.1
	IL2RG	NM_001438870.1		c.325G>A	p.Glu109Lys	missense	Exon 3 of 7	NP_001425799.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IL2RG	ENST00000374202.7	TSL:1 MANE Select	c.325G>A	p.Glu109Lys	missense	Exon 3 of 8	ENSP00000363318.3
ENSG00000285171	ENST00000646505.1		n.325G>A		non_coding_transcript_exon	Exon 3 of 12	ENSP00000496673.1
IL2RG	ENST00000482750.6	TSL:5	c.325G>A	p.Glu109Lys	missense	Exon 3 of 7	ENSP00000421262.2

Frequencies

GnomAD3 genomes

AF:

0.000600

AC:

AN:

111633

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000900

AC:

165

AN:

183382

AF XY:

0.000796

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 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

African (AFR)

AF:

0.000114

AC:

AN:

26360

American (AMR)

AF:

0.0000284

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00103

AC:

AN:

19372

East Asian (EAS)

AF:

0.00

AC:

AN:

30193

South Asian (SAS)

AF:

0.000702

AC:

AN:

54106

European-Finnish (FIN)

AF:

0.00412

AC:

167

AN:

40531

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.000697

AC:

585

AN:

839864

Other (OTH)

AF:

0.000434

AC:

AN:

46033

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

129

161

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000600

AC:

AN:

111686

Hom.:

Cov.:

AF XY:

0.000738

AC XY:

AN XY:

33878

show subpopulations

African (AFR)

AF:

0.0000325

AC:

AN:

30723

American (AMR)

AF:

0.00

AC:

AN:

10472

Ashkenazi Jewish (ASJ)

AF:

0.00114

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3568

South Asian (SAS)

AF:

0.000740

AC:

AN:

2704

European-Finnish (FIN)

AF:

0.00298

AC:

AN:

6033

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.000809

AC:

AN:

53127

Other (OTH)

AF:

0.00

AC:

AN:

1519

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000737

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

ClinVar submissions as Germline

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

X-linked severe combined immunodeficiency (4)

not specified (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.62

DEOGEN2

Uncertain

0.53

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.70

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.0052

MetaSVM

Benign

-0.48

MutationAssessor

Benign

1.1

PhyloP100

0.25

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.080

REVEL

Benign

0.28

Sift

Benign

0.94

Sift4G

Benign

0.76

Polyphen

0.0

Vest4

0.066

MVP

0.79

MPC

0.66

ClinPred

0.011

GERP RS

1.5

PromoterAI

-0.021

Neutral

(source)

Varity_R

0.14

gMVP

0.86

Mutation Taster

=97/3

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over