Variant: NM_000206.3(IL2RG):c.455-2A>C

CA413496514

947759 (ClinVar)

Gene: IL2RG

Condition: T-B+ severe combined immunodeficiency due to gamma chain deficiency

Inheritance Mode: X-linked inheritance

UUID: a4071df3-224e-4a87-9c19-08426a2c7c14

Approved on: 2024-03-08

Published on: 2024-03-08

HGVS expressions

NM_000206.3:c.455-2A>C
NM_000206.3(IL2RG):c.455-2A>C
NC_000023.11:g.71110297T>G
CM000685.2:g.71110297T>G
NC_000023.10:g.70330147T>G
CM000685.1:g.70330147T>G
NC_000023.9:g.70246872T>G
NG_009088.1:g.6257A>C
NG_021141.1:g.1492A>C
ENST00000482750.6:c.455-2A>C
ENST00000696903.1:n.506-2A>C
ENST00000374202.7:c.455-2A>C
ENST00000642473.1:n.819-2A>C
ENST00000644022.1:n.860+207A>C
ENST00000644708.1:n.861-2A>C
ENST00000644911.1:n.861-2A>C
ENST00000645266.1:c.455-2A>C
ENST00000645518.1:c.455-2A>C
ENST00000646106.1:c.455-2A>C
ENST00000646505.1:c.455-2A>C
ENST00000647492.1:c.455-2A>C
ENST00000276110.6:n.1046A>C
ENST00000374188.7:c.-262-2A>C
ENST00000374202.6:c.455-2A>C
ENST00000456850.6:c.25-907A>C
ENST00000464642.5:c.323-2A>C
ENST00000487883.1:c.419-2A>C
ENST00000512747.3:n.521+207A>C
NM_000206.2:c.455-2A>C

Pathogenic

• Met criteria codes: PM2_Supporting PS1 PVS1

Expert Panel

Severe Combined Immunodeficiency Disease VCEP

Criteria Specification Information

Criteria Specification: ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for IL2RG Version 1.0.0

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The NM_000206.3:c.455-2A>C variant in IL2RG occurs within the canonical splice acceptor site (-2) of intron 3. It is predicted to cause skipping of biologically relevant exon 4 (SpliceAI score 0.59), resulting in a frameshift leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent from gnomAD v2.1.1 and gnomAD v4.0 (PM2_Supporting). The variant has not been reported in the literature in individuals with SCID. However, it is located in the splice consensus sequence at the same nucleotide position as a pathogenic variant classified by SCID VCEP specification, NM_000206.3:c.455-2A>T (PS1). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1, PM2_Supporting, PS1. (VCEP specifications version 1)

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v2.1.1 and gnomAD v4.0. (PM2_Supporting)
• PS1: The variant locates in the splice consensus sequence, at the same nucleotide position as a pathogenic variant classified by SCID VCEP specification, NM_000206.3:c.455-2A>T. The predicted impact scores by SpliceAI are equal between the two variants. PS1 is met.
• PVS1: The NM_000206.3:c.455-2A>C variant in IL2RG occurs within the canonical splice acceptor site (-2) of intron 3. It is predicted to cause skipping of biologically relevant exon 4 (SpliceAI score 0.59), resulting in a frameshift leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. (PVS1)