NM_000206.3:c.1076C>T

Variant names:

Variant summary

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

This summary comes from the ClinGen Evidence Repository: NM_000206.3(IL2RG):c.1076C>T is a missense variant predicted to cause substitution of Alanine by Valine at amino acid 359 (p.Ala359Val). The highest population minor allele frequency in gnomAD v4 is 0.0001453 (126/867358) in European Non-Finnish population (PM2_Supporting, BS1, and BA1 are not met). 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 a variant of uncertain significance for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: None (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA331121466/MONDO:0010315/129

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.00012 ( 0 hom. 43 hem. )

Consequence

IL2RG
NM_000206.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:3B:1

Conservation

PhyloP100: 1.10

Publications

0 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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RG	NM_000206.3 link	c.1076C>T	p.Ala359Val	missense_variant	Exon 8 of 8	ENST00000374202.7	NP_000197.1	P31785-1
IL2RG	NM_001438870.1 link	c.*196C>T		3_prime_UTR_variant	Exon 7 of 7		NP_001425799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL2RG	ENST00000374202.7 link	c.1076C>T	p.Ala359Val	missense_variant	Exon 8 of 8	1	NM_000206.3	ENSP00000363318.3		P31785-1
ENSG00000285171	ENST00000646505.1 link	n.924+507C>T		intron_variant	Intron 7 of 11			ENSP00000496673.1		A0A2R8YE73

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000324

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000223

AC:

AN:

134575

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000841

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:

0.0000313

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000122

AC:

127

AN:

1039816

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

332752

show subpopulations

African (AFR)

AF:

0.0000413

AC:

AN:

24189

American (AMR)

AF:

0.00

AC:

AN:

24798

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15728

East Asian (EAS)

AF:

0.00

AC:

AN:

29618

South Asian (SAS)

AF:

0.00

AC:

AN:

45544

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38434

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3848

European-Non Finnish (NFE)

AF:

0.000154

AC:

125

AN:

814207

Other (OTH)

AF:

0.0000230

AC:

AN:

43450

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112264

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34420

show subpopulations

African (AFR)

AF:

0.0000324

AC:

AN:

30858

American (AMR)

AF:

0.00

AC:

AN:

10737

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3542

South Asian (SAS)

AF:

0.00

AC:

AN:

2730

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53151

Other (OTH)

AF:

0.00

AC:

AN:

1515

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000437

Hom.:

Bravo

AF:

0.0000264

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

X-linked severe combined immunodeficiency

Uncertain:2Benign:1

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 10, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

NM_000206.3(IL2RG):c.1076C>T is a missense variant predicted to cause substitution of Alanine by Valine at amino acid 359 (p.Ala359Val). The highest population minor allele frequency in gnomAD v4 is 0.0001453 (126/867358) in European Non-Finnish population (PM2_Supporting, BS1, and BA1 are not met). 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 a variant of uncertain significance for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: None (VCEP specifications version 1). -

Inborn genetic diseases

Uncertain:1

Dec 15, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1076C>T (p.A359V) alteration is located in exon 8 (coding exon 8) of the IL2RG gene. This alteration results from a C to T substitution at nucleotide position 1076, causing the alanine (A) at amino acid position 359 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.44

T;.;.

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.82

T;T;T

M_CAP

Benign

0.063

MetaRNN

Benign

0.089

T;T;T

MetaSVM

Uncertain

0.22

MutationAssessor

Benign

1.9

M;.;.

PhyloP100

1.1

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.31

N;N;N

REVEL

Benign

0.19

Sift

Benign

0.28

T;T;T

Sift4G

Benign

0.30

T;T;T

Polyphen

0.0010

B;B;.

Vest4

0.10

MutPred

0.20

Loss of disorder (P = 0.0448);.;.;

MVP

0.67

MPC

0.78

ClinPred

0.018

GERP RS

2.4

Varity_R

0.056

gMVP

0.41

Mutation Taster

=91/9

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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NM_000206.3:c.1076C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over