Genetic Variant NM_000206.3:c.1076C>A (chrX-71107770-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000206.3(IL2RG):c.1076C>A(p.Ala359Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000962 in 1,039,816 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A359V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 9.6e-7 ( 0 hom. 0 hem. )

Consequence

IL2RG
NM_000206.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16218063).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RG	NM_000206.3 link	c.1076C>A	p.Ala359Asp	missense_variant	Exon 8 of 8	ENST00000374202.7	NP_000197.1	P31785-1
IL2RG	NM_001438870.1 link	c.*196C>A		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>A	p.Ala359Asp	missense_variant	Exon 8 of 8	1	NM_000206.3	ENSP00000363318.3		P31785-1
ENSG00000285171	ENST00000646505.1 link	n.924+507C>A		intron_variant	Intron 7 of 11			ENSP00000496673.1		A0A2R8YE73

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.62e-7

AC:

AN:

1039816

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

332752

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24189

American (AMR)

AF:

0.00

AC:

AN:

24798

Ashkenazi Jewish (ASJ)

AF:

0.0000636

AC:

AN:

15728

East Asian (EAS)

AF:

0.00

AC:

AN:

29618

South Asian (SAS)

AF:

0.00

AC:

AN:

45545

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38434

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3848

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

814206

Other (OTH)

AF:

0.00

AC:

AN:

43450

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.072

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

T;.;.

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.74

T;T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

1.9

M;.;.

PhyloP100

1.1

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.20

N;N;N

REVEL

Benign

0.21

Sift

Uncertain

0.018

D;D;D

Sift4G

Uncertain

0.013

D;D;D

Polyphen

0.42

B;B;.

Vest4

0.23

MutPred

0.12

Gain of loop (P = 0.0435);.;.;

MVP

0.69

MPC

1.5

ClinPred

0.56

GERP RS

2.4

Varity_R

0.23

gMVP

0.58

Mutation Taster

=90/10

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over