X-71107754-GGT-G

Variant names:

• chrX-71107754-GGT-G
• NM_000206.3:c.1090_1091delAC

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PVS1_Moderate BS2

The NM_000206.3(IL2RG):​c.1090_1091delAC​(p.Thr364ProfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000388 in 1,030,833 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T364T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000039 (0 hom. 2 hem.)
• Consequence: IL2RG NM_000206.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16
• Publications: 0 publications found

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

ENSG00000285171 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.018 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RG	NM_000206.3	c.1090_1091delAC	p.Thr364ProfsTer4	frameshift_variant	Exon 8 of 8	ENST00000374202.7	NP_000197.1
IL2RG	NM_001438870.1	c.*210_*211delAC		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	c.1090_1091delAC	p.Thr364ProfsTer4	frameshift_variant	Exon 8 of 8	1	NM_000206.3	ENSP00000363318.3
ENSG00000285171	ENST00000646505.1	n.924+521_924+522delAC		intron_variant	Intron 7 of 11			ENSP00000496673.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000388 AC: 4 AN: 1030833 Hom.: 0 AF XY: 0.00000608 AC XY: 2 AN XY: 328739

African (AFR) AF: 0.00 AC: 0 AN: 23956

American (AMR) AF: 0.00 AC: 0 AN: 23581

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15229

East Asian (EAS) AF: 0.00 AC: 0 AN: 29447

South Asian (SAS) AF: 0.00 AC: 0 AN: 44088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3796

European-Non Finnish (NFE) AF: 0.00000494 AC: 4 AN: 809631

Other (OTH) AF: 0.00 AC: 0 AN: 43049

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked severe combined immunodeficiency Uncertain:1

Jun 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Thr364Profs*4) in the IL2RG gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 6 amino acid(s) of the IL2RG protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IL2RG-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2

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

Other links and lift over

hg19: chrX-70327604;