Genetic Variant IL2RG:c.115+153C>T (chrX-71111272-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000206.3(IL2RG):c.115+153C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 739,642 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 36 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.00013 ( 0 hom. 33 hem. )

Consequence

IL2RG
NM_000206.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.74

Publications

1 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000454 (5/110168) while in subpopulation EAS AF = 0.000854 (3/3511). AF 95% confidence interval is 0.000233. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 3 XL,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RG	NM_000206.3	MANE Select	c.115+153C>T		intron	N/A	NP_000197.1
	IL2RG	NM_001438870.1		c.115+153C>T		intron	N/A	NP_001425799.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
IL2RG	ENST00000374202.7	TSL:1 MANE Select	c.115+153C>T	intron	N/A	ENSP00000363318.3
ENSG00000285171	ENST00000646505.1		n.115+153C>T	intron	N/A	ENSP00000496673.1
IL2RG	ENST00000276110.6	TSL:2	n.279C>T	non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes

AF:

0.0000454

AC:

AN:

110115

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:

0.000852

Gnomad SAS

AF:

0.000376

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000191

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000127

AC:

AN:

629474

Hom.:

Cov.:

AF XY:

0.000204

AC XY:

AN XY:

161730

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15958

American (AMR)

AF:

0.00

AC:

AN:

19941

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12727

East Asian (EAS)

AF:

0.00115

AC:

AN:

25231

South Asian (SAS)

AF:

0.000741

AC:

AN:

35099

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30524

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1910

European-Non Finnish (NFE)

AF:

0.0000349

AC:

AN:

458249

Other (OTH)

AF:

0.000302

AC:

AN:

29835

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.0000454

AC:

AN:

110168

Hom.:

Cov.:

AF XY:

0.0000918

AC XY:

AN XY:

32692

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30382

American (AMR)

AF:

0.00

AC:

AN:

10399

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2600

East Asian (EAS)

AF:

0.000854

AC:

AN:

3511

South Asian (SAS)

AF:

0.000378

AC:

AN:

2649

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5860

Middle Eastern (MID)

AF:

0.00

AC:

AN:

211

European-Non Finnish (NFE)

AF:

0.0000191

AC:

AN:

52385

Other (OTH)

AF:

0.00

AC:

AN:

1492

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000712

Hom.:

Bravo

AF:

0.000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.029

(source)

DANN

Benign

0.40

PhyloP100

-1.7

PromoterAI

-0.047

Neutral

(source)

Mutation Taster

=100/0

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

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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