Variant: NM_000536.4(RAG2):c.955G>T (p.Gly319Ter)

CA220579698

500475 (ClinVar)

Gene: RAG2

Condition: recombinase activating gene 2 deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 51af7bdf-04dc-48ca-b682-c0fbebfaae5f

Approved on: 2024-01-17

Published on: 2024-01-17

HGVS expressions

NM_000536.4:c.955G>T
NM_000536.4(RAG2):c.955G>T (p.Gly319Ter)
NC_000011.10:g.36593214C>A
CM000673.2:g.36593214C>A
NC_000011.9:g.36614764C>A
CM000673.1:g.36614764C>A
NC_000011.8:g.36571340C>A
NG_007573.1:g.10023G>T
NG_033154.1:g.3722C>A
ENST00000311485.8:c.955G>T
ENST00000311485.7:c.955G>T
ENST00000524423.1:n.131+4888G>T
ENST00000618712.4:c.955G>T
NM_000536.3:c.955G>T
NM_001243785.1:c.955G>T
NM_001243786.1:c.955G>T
NM_001243785.2:c.955G>T
NM_001243786.2:c.955G>T

Likely Pathogenic

• Met criteria codes: PVS1 PM2_Supporting

• Not Met criteria codes: PS4

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 RAG2 Version 1.0.0

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The NM_000536.4:c.955G>T variant in RAG2 is a nonsense variant predicted to result in a truncated protein (p.Gly319*). Although this variant is expected to escape nonsense-mediated decay (NMD), it would be expected to disrupt approximately 40% of the RAG2 protein. In addition, this variant would be expected to disrupt/remove the entire PHD domain (amino acids 414-487), which is defined as a mutational hotspot/critical functional domain by the ClinGen SCID VCEP (PMID: 15964836). PVS1 met. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, the variant has not been identified in the literature in patients/case reports or functional studies. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2 and PVS1 (VCEP specifications version 1).

Met criteria codes

• PVS1: This truncation Gly319* is not expected to undergo nonsense-mediated decay (NMD) but would be expected to remove around 40% of the total RAG2 protein (would remove 209/527 amino acids). In addition, it would remove the entire PHD domain (amino acids 414-487), which is defined by the SCID VCEP as a region critical to RAG2 protein function (PMID: 15964836). Therefore PVS1 is met.
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

Not Met criteria codes

• PS4: To our knowledge, the variant has not been identified in the literature in SCID patients.