X-71110552-G-A

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

1
7
9

Clinical Significance

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

Conservation

PhyloP100: -0.356
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]

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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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IL2RGNM_000206.3 linkc.406C>T p.Arg136Trp missense_variant Exon 3 of 8 ENST00000374202.7 NP_000197.1 P31785-1
IL2RGXM_047442089.1 linkc.406C>T p.Arg136Trp missense_variant Exon 3 of 7 XP_047298045.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IL2RGENST00000374202.7 linkc.406C>T p.Arg136Trp missense_variant Exon 3 of 8 1 NM_000206.3 ENSP00000363318.3 P31785-1
ENSG00000285171ENST00000646505.1 linkn.406C>T non_coding_transcript_exon_variant Exon 3 of 12 ENSP00000496673.1 A0A2R8YE73

Frequencies

GnomAD3 genomes
AF:
0.00000894
AC:
1
AN:
111807
Hom.:
0
Cov.:
22
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:
1
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:
22
AN:
1097861
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
4
AN XY:
363219
show subpopulations
Gnomad4 AFR exome
AF:
0.000152
AC:
4
AN:
26393
Gnomad4 AMR exome
AF:
0.000114
AC:
4
AN:
35207
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
19382
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
30204
Gnomad4 SAS exome
AF:
0.0000185
AC:
1
AN:
54135
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
40534
Gnomad4 NFE exome
AF:
0.0000143
AC:
12
AN:
841789
Gnomad4 Remaining exome
AF:
0.0000217
AC:
1
AN:
46084
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
2
4
6
8
10
<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:
1
AN:
111807
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
33983
show subpopulations
Gnomad4 AFR
AF:
0.0000325
AC:
0.0000325055
AN:
0.0000325055
Gnomad4 AMR
AF:
0.00
AC:
0
AN:
0
Gnomad4 ASJ
AF:
0.00
AC:
0
AN:
0
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.00
AC:
0
AN:
0
Gnomad4 OTH
AF:
0.00
AC:
0
AN:
0
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Variant carriers
0
2
4
6
8
10
<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.:
0
Bravo
AF:
0.0000453
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000346
AC:
1

ClinVar

Significance: Likely benign
Submissions summary: Uncertain:1Benign:2
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

X-linked severe combined immunodeficiency Uncertain:1Benign:2
Jun 13, 2024
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen
Significance:Likely benign
Review Status:reviewed by expert panel
Collection Method:curation

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). -

Apr 11, 2020
Natera, Inc.
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jul 12, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.81
D;.
FATHMM_MKL
Benign
0.12
N
LIST_S2
Benign
0.82
T;T
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.25
T;T
MetaSVM
Benign
-0.51
T
MutationAssessor
Uncertain
2.1
M;.
PrimateAI
Benign
0.23
T
PROVEAN
Uncertain
-2.5
D;D
REVEL
Uncertain
0.45
Sift
Uncertain
0.023
D;D
Sift4G
Uncertain
0.023
D;.
Polyphen
1.0
D;.
Vest4
0.095
MutPred
0.46
Loss of disorder (P = 0.0063);.;
MVP
0.85
MPC
0.63
ClinPred
0.36
T
GERP RS
-2.6
Varity_R
0.29
gMVP
0.77
Mutation Taster
=89/11
polymorphism

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs758080286; hg19: chrX-70330402; COSMIC: COSV104370509; COSMIC: COSV104370509; API