rs758080286

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: The c.406C>T (NM_000206.3) variant in IL2RG is a missense variant predicted to cause the substitution of Arginine by Tryptophan at amino acid 136 (p.Arg136Trp).The filtering allele frequency (the upper threshold of the 95% CI of 5/57157 alleles) of the c.406C>T variant in IL2RG is 0.00003386 for African/African American chromosomes by gnomAD v4.1.0, which is lower than the ClinGen SCID VCEP threshold (<0.000124) for PM2_Supporting. However, 04 hemizygotes were observed in gnomAD; thus, PM2 was not met, and BS2 is applicable.In summary, this variant meets the criteria to be classified as Likely Benign for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BS2 (VCEP specifications version 1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA330970071/MONDO:0010315/129

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000020 ( 0 hom. 4 hem. )

Consequence

IL2RG
NM_000206.3 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:2

Conservation

PhyloP100: -0.356

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: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, 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: Likely_benign. The variant received -4 ACMG points.

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.406C>T	p.Arg136Trp	missense	Exon 3 of 8	NP_000197.1	P31785-1
	IL2RG	NM_001438870.1		c.406C>T	p.Arg136Trp	missense	Exon 3 of 7	NP_001425799.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL2RG	ENST00000374202.7	TSL:1 MANE Select	c.406C>T	p.Arg136Trp	missense	Exon 3 of 8	ENSP00000363318.3	P31785-1
ENSG00000285171	ENST00000646505.1		n.406C>T		non_coding_transcript_exon	Exon 3 of 12	ENSP00000496673.1	A0A2R8YE73
IL2RG	ENST00000482750.6	TSL:5	c.406C>T	p.Arg136Trp	missense	Exon 3 of 7	ENSP00000421262.2	H0Y8J6

Frequencies

GnomAD3 genomes

AF:

0.00000894

AC:

AN:

111807

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000325

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:

0.00000545

AC:

AN:

183488

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000760

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000200

AC:

AN:

1097861

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

363219

show subpopulations

African (AFR)

AF:

0.000152

AC:

AN:

26393

American (AMR)

AF:

0.000114

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54135

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.0000143

AC:

AN:

841789

Other (OTH)

AF:

0.0000217

AC:

AN:

46084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

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:

0.00000894

AC:

AN:

111807

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33983

show subpopulations

African (AFR)

AF:

0.0000325

AC:

AN:

30764

American (AMR)

AF:

0.00

AC:

AN:

10521

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3589

South Asian (SAS)

AF:

0.00

AC:

AN:

2686

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6035

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53134

Other (OTH)

AF:

0.00

AC:

AN:

1506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.00

Hom.:

Bravo

AF:

0.0000453

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

X-linked severe combined immunodeficiency (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.82

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.1

PhyloP100

-0.36

PrimateAI

Benign

0.23

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.45

Sift

Uncertain

0.023

Sift4G

Uncertain

0.023

Polyphen

1.0

Vest4

0.095

MutPred

0.46

Loss of disorder (P = 0.0063)

MVP

0.85

MPC

0.63

ClinPred

0.36

GERP RS

-2.6

PromoterAI

-0.015

Neutral

(source)

Varity_R

0.29

gMVP

0.77

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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