chrX-71110552-G-A

Position:

chrX-71110552-G-A

Variant summary

Our verdict is Likely benign. Variant got -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
ENST00000374202.7 missense

Scores

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]

IL2RG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL2RG	NM_000206.3 linkuse as main transcript	c.406C>T	p.Arg136Trp	missense_variant	3/8	ENST00000374202.7	NP_000197.1
IL2RG	XM_047442089.1 linkuse as main transcript	c.406C>T	p.Arg136Trp	missense_variant	3/7		XP_047298045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL2RG	ENST00000374202.7 linkuse as main transcript	c.406C>T	p.Arg136Trp	missense_variant	3/8	1	NM_000206.3	ENSP00000363318	P1	P31785-1

Frequencies

GnomAD3 genomes

AF:

0.00000894

AC:

AN:

111807

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33983

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

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183488

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67932

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 SAS 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

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000143

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.00000894

AC:

AN:

111807

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33983

show subpopulations

Gnomad4 AFR

AF:

0.0000325

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

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

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 11, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	- -
Likely benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jun 13, 2024	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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;.

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.82

T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.1

M;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.23

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

GERP RS

-2.6

Varity_R

0.29

gMVP

0.77

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over