Genetic Variant IL2RG:p.Cys362MetfsTer7 (chrX-71107763-T-TG) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PVS1_ModerateBS2

The NM_000206.3(IL2RG):c.1082dupC(p.Cys362MetfsTer7) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000087 in 1,149,082 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.0000077 ( 0 hom. 2 hem. )

Consequence

IL2RG
NM_000206.3 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.00

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0252 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

BS2

High Hemizygotes in GnomAdExome4 at 2 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RG	NM_000206.3 link	c.1082dupC	p.Cys362MetfsTer7	frameshift_variant	Exon 8 of 8	ENST00000374202.7	NP_000197.1	P31785-1
IL2RG	NM_001438870.1 link	c.*202dupC		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.1082dupC	p.Cys362MetfsTer7	frameshift_variant	Exon 8 of 8	1	NM_000206.3	ENSP00000363318.3		P31785-1
ENSG00000285171	ENST00000646505.1 link	n.924+513dupC		intron_variant	Intron 7 of 11			ENSP00000496673.1		A0A2R8YE73

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111832

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000651

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000228

AC:

AN:

131677

AF XY:

0.0000240

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000592

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000319

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000771

AC:

AN:

1037250

Hom.:

Cov.:

AF XY:

0.00000602

AC XY:

AN XY:

332108

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24109

American (AMR)

AF:

0.00

AC:

AN:

24390

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15553

East Asian (EAS)

AF:

0.00

AC:

AN:

29578

South Asian (SAS)

AF:

0.00

AC:

AN:

45114

European-Finnish (FIN)

AF:

0.0000522

AC:

AN:

38296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3835

European-Non Finnish (NFE)

AF:

0.00000738

AC:

AN:

813025

Other (OTH)

AF:

0.00

AC:

AN:

43350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111832

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34066

show subpopulations

African (AFR)

AF:

0.0000651

AC:

AN:

30719

American (AMR)

AF:

0.00

AC:

AN:

10687

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3530

South Asian (SAS)

AF:

0.00

AC:

AN:

2700

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6130

Middle Eastern (MID)

AF:

0.00

AC:

AN:

235

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52995

Other (OTH)

AF:

0.00

AC:

AN:

1507

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.0

Mutation Taster

=49/151

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over