NM_000206.3:c.821T>C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1_StrongPM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000206.3(IL2RG):c.821T>C (p.Ile274Thr) 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. This variant introduces a polar residue within the transmembrane region (amino acids 263-283) of IL2RG, which is defined as a critical functional domain by the ClinGen SCID VCEP (PM1_Strong).The filtering allele frequency (the upper threshold of the 95% CI of 2/70896) of the c.821T>C variant in IL2RG is 0.000004680 for European (non- Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.000124; PM2_Supporting). In summary, this variant is classified as uncertain significance due to insufficient information. Criteria applied: PM1_strong and PM2_supporting (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10443808/MONDO:0010315/129

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000083 ( 0 hom. 6 hem. )

Consequence

IL2RG
NM_000206.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:8

Conservation

PhyloP100: 4.18

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

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

PM2

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.821T>C	p.Ile274Thr	missense	Exon 6 of 8	NP_000197.1
	IL2RG	NM_001438870.1		c.758-286T>C		intron	N/A	NP_001425799.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IL2RG	ENST00000374202.7	TSL:1 MANE Select	c.821T>C	p.Ile274Thr	missense	Exon 6 of 8	ENSP00000363318.3
ENSG00000285171	ENST00000646505.1		n.821T>C		non_coding_transcript_exon	Exon 6 of 12	ENSP00000496673.1
IL2RG	ENST00000482750.6	TSL:5	c.758-286T>C		intron	N/A	ENSP00000421262.2

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112507

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:

0.0000563

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000122

AC:

AN:

163372

AF XY:

0.00

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:

0.0000282

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000831

AC:

AN:

1083366

Hom.:

Cov.:

AF XY:

0.0000170

AC XY:

AN XY:

353146

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25531

American (AMR)

AF:

0.00

AC:

AN:

34771

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19283

East Asian (EAS)

AF:

0.00

AC:

AN:

28894

South Asian (SAS)

AF:

0.00

AC:

AN:

52085

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40081

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4122

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

833061

Other (OTH)

AF:

0.00

AC:

AN:

45538

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.0000267

AC:

AN:

112507

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34663

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30943

American (AMR)

AF:

0.00

AC:

AN:

10601

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2658

East Asian (EAS)

AF:

0.00

AC:

AN:

3614

South Asian (SAS)

AF:

0.00

AC:

AN:

2748

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6189

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000563

AC:

AN:

53308

Other (OTH)

AF:

0.00

AC:

AN:

1518

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000142

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00000831

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

X-linked severe combined immunodeficiency (3)

IL2RG-related disorder (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.64

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.66

M_CAP

Pathogenic

0.35

MetaRNN

Uncertain

0.72

MetaSVM

Uncertain

0.59

MutationAssessor

Uncertain

2.5

PhyloP100

4.2

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.44

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0060

Polyphen

0.65

Vest4

0.52

MVP

0.97

MPC

1.3

ClinPred

0.82

GERP RS

4.9

Varity_R

0.14

gMVP

0.87

Mutation Taster

=93/7

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