Variant: NM_000536.4(RAG2):c.115A>G (p.Arg39Gly)

CA122867

13136 (ClinVar)

Gene: RAG2

Condition: recombinase activating gene 2 deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 418ca304-b22e-4a9e-a014-7abfa82d833c

Approved on: 2024-02-26

Published on: 2024-02-26

HGVS expressions

NM_000536.4:c.115A>G
NM_000536.4(RAG2):c.115A>G (p.Arg39Gly)
NC_000011.10:g.36594054T>C
CM000673.2:g.36594054T>C
NC_000011.9:g.36615604T>C
CM000673.1:g.36615604T>C
NC_000011.8:g.36572180T>C
NG_007573.1:g.9183A>G
NG_033154.1:g.4562T>C
ENST00000527033.6:c.115A>G
ENST00000529083.2:c.115A>G
ENST00000532616.2:c.115A>G
ENST00000311485.8:c.115A>G
ENST00000311485.7:c.115A>G
ENST00000524423.1:n.131+4048A>G
ENST00000527033.5:c.115A>G
ENST00000529083.1:c.115A>G
ENST00000618712.4:c.115A>G
NM_000536.3:c.115A>G
NM_001243785.1:c.115A>G
NM_001243786.1:c.115A>G
NM_001243785.2:c.115A>G
NM_001243786.2:c.115A>G

Pathogenic

• Met criteria codes: PP4 PS3_Moderate PM2_Supporting PP1_Moderate PM3_Strong PM1_Supporting

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

NM_000536.4(RAG2):c.115A>G is a missense variant predicted to cause substitution of Arginine by Glycine at amino acid 39 (p.Arg39Gly).This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting).The variant is absent in gnomAD v4 (PM2_supporting). Patient with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.),T-B-NK+ lymphocyte subset profile (0.5 pt.) :Total :1.5 pts. PP4 met (PMID: 11313270). This variant was found to segregate in 2 affected siblings from one family (PP1_moderate) (PMID: 11313270).Two patients (PMID: 11313270) were found compound heterozygous for R39G and R229Q (pathogenic variant) ;total : 2pts. (PM3_strong).This variant showed <25 % of wild type activity in In vitro V(D)J recombination assay (PS3_moderate) (PMID: 11313270). In summary, this variant meets the criteria to be classified as a Pathogenic variant for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_supporting,PM2_supporting,PP4 met,PP1_moderate,PM3_strong,PS3_moderate(VCEP specifications version 1).

Met criteria codes

• PP4: Patient with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.),T-B-NK+ lymphocyte subset profile (0.5 pt.) :Total :1.5 pts. PP4 met (PMID: 11313270)
• PS3_Moderate: This variant showed <25 % of wild type activity in In vitro V(D)J recombination assay (PS3_moderate) (PMID: 11313270).
• PM2_Supporting: The variant is absent in gnomAD v4 (PM2_supporting).
• PP1_Moderate: This variant was found to segregate in 2 affected siblings from one family (PP1_moderate) (PMID: 11313270).
• PM3_Strong: Two patients ( PMID: 11313270) were found compound heterozygous for R39G and R229Q (pathogenic variant) ;total : 2pts. (PM3_strong)
• PM1_Supporting: This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting).