Variant: NM_000536.4(RAG2):c.1247G>T (p.Trp416Leu)

CA214212

36717 (ClinVar)

Gene: RAG2

Condition: recombinase activating gene 2 deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 89f43e11-beb2-4647-8c50-9150c12f172e

Approved on: 2024-04-01

Published on: 2024-04-01

HGVS expressions

NM_000536.4:c.1247G>T
NM_000536.4(RAG2):c.1247G>T (p.Trp416Leu)
NC_000011.10:g.36592922C>A
CM000673.2:g.36592922C>A
NC_000011.9:g.36614472C>A
CM000673.1:g.36614472C>A
NC_000011.8:g.36571048C>A
NG_007573.1:g.10315G>T
NG_033154.1:g.3430C>A
ENST00000527033.6:c.1247G>T
ENST00000529083.2:c.1247G>T
ENST00000532616.2:c.1247G>T
ENST00000311485.8:c.1247G>T
ENST00000311485.7:c.1247G>T
ENST00000524423.1:n.131+5180G>T
ENST00000534663.1:c.*86-45C>A
ENST00000618712.4:c.1247G>T
NM_000536.3:c.1247G>T
NM_001243785.1:c.1247G>T
NM_001243786.1:c.1247G>T
NM_001243785.2:c.1247G>T
NM_001243786.2:c.1247G>T

Likely Pathogenic

• Met criteria codes: PP4 PM3 PM1 PS3_Moderate

• Not Met criteria codes: PM2 BA1 BS2 BS1

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 c.1247G>T (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Tryptophan by Leucine at amino acid 416 (p.Trp416Leu). The Popmax Filtering AF (95% confidence) in gnomAD v.4 is 0.0002998, based on 36/91078 alleles in the South Asian population. PM2_Supporting (<0.0000588), BS1 (>0.00195), and BA1 (>0.00872) are not met. No homozygotes have been observed in gnomAD (BS2 is not met). This variant is located in the PHD domain, amino acids 414-487 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1. The variant was found in at least four individuals in the literature, with diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met. All of them are homozygous, reaching 1 point for homozygous occurrence. PM3_Moderate (PMID: 17572155). Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5pts + T-B-NK+ lymphocyte subset profile 0.5pts; the total is 1 point, PP4 is met (PMID: 29772310). The recombination activity assay showed activity of this variant compared to wildtype RAG2 is 1.4% (SEM 0.2), which is lower than the SCID VCEP threshold (<25%) for PS3_Moderate, meeting this criterion (PS3_Moderate, PMID 29772310). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM1, PM3, PP4, and PS3_Moderate (VCEP specifications version 1.0).

Met criteria codes

• PP4: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5pts + T-B-NK+ lymphocyte subset profile 0.5pts, the total is 1 point, PP4 is met (P33, PMID: 29772310).
• PM3: The variant was found in at least four individuals in the literature, with diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met. All of them are homozygous, reaching 1 point for homozygous occurrence. PM3_Moderate (PMID: 17572155).
• PM1: This variant is located in the PHD domain, amino acids 414-487 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1_Moderate.
• PS3_Moderate: The recombination activity assay showed activity of this variant compared to wildtype RAG2 is 1.4% (SEM 0.2), which is lower than the SCID VCEP threshold (<25%) for PS3_Moderate, meeting this criterion (PS3_Moderate, PMID 29772310).

Not Met criteria codes

• PM2: The Popmax Filtering AF (95% confidence) in gnomAD v.4 is 0.0002998, based on 36/91078 alleles in the South Asian population. PM2_Supporting (<0.0000588), BS1 (>0.00195), and BA1 (>0.00872) are not met. No homozygotes have been observed in gnomAD.
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline