chrX-71107785-T-C
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS1
The NM_000206.3(IL2RG):c.1061A>G(p.His354Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,063,540 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).
Frequency
Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 23)
Exomes 𝑓: 0.000011 ( 0 hom. 4 hem. )
Failed GnomAD Quality Control
Consequence
IL2RG
NM_000206.3 missense
NM_000206.3 missense
Scores
2
9
6
Clinical Significance
Conservation
PhyloP100: 1.37
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 made for transcript
Verdict is Benign. Variant got -14 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.16674474).
BP6
?
Variant X-71107785-T-C is Benign according to our data. Variant chrX-71107785-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1199323.Status of the report is reviewed_by_expert_panel, 3 stars.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000113 (12/1063540) while in subpopulation EAS AF= 0.000234 (7/29909). AF 95% confidence interval is 0.00011. There are 0 homozygotes in gnomad4_exome. There are 4 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IL2RG | NM_000206.3 | c.1061A>G | p.His354Arg | missense_variant | 8/8 | ENST00000374202.7 | |
IL2RG | XM_047442089.1 | c.*181A>G | 3_prime_UTR_variant | 7/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IL2RG | ENST00000374202.7 | c.1061A>G | p.His354Arg | missense_variant | 8/8 | 1 | NM_000206.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 0AN: 112438Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 34604 FAILED QC
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GnomAD3 exomes AF: 0.0000201 AC: 3AN: 148907Hom.: 0 AF XY: 0.0000217 AC XY: 1AN XY: 46051
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GnomAD4 exome AF: 0.0000113 AC: 12AN: 1063540Hom.: 0 Cov.: 29 AF XY: 0.0000117 AC XY: 4AN XY: 343020
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GnomAD4 genome ? Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 112438Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 34604
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ClinVar
Significance: Likely benign
Submissions summary: Uncertain:2Benign:2
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
X-linked severe combined immunodeficiency Uncertain:1Benign:2
Likely benign, reviewed by expert panel | curation | ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen | Jan 26, 2024 | NM_000206.3(IL2RG):c.1061A>G is a missense variant predicted to cause substitution of Histidine by Arginine at amino acid 354 (p.His354Arg). The filtering allele frequency (the upper threshold of the 95% CI of 7/30447) of the c.1061A>G variant in IL2RG is 0.0001216 for East Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.000124 ) for PM2_Supporting. However, 4 hemizygotes were reported (PM2 not met).The variant is observed in 4 hemizygotes in gnomAD v4 (BS2_Strong). To our knowledge, this variant has not been reported in the literature in individuals affected with IL2RG related conditions or in functional studies. In summary, this variant meets the criteria to be classified as likely benign variant for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS2 (VCEP specifications version 1). - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Aug 18, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 14, 2021 | - - |
Combined immunodeficiency, X-linked Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 14, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Uncertain
DEOGEN2
Uncertain
D;.;.
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;.
MutationTaster
Benign
N;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;D;N
REVEL
Uncertain
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;D;.
Vest4
MutPred
Gain of loop (P = 0.0435);.;.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at