Variant: NM_000536.4(RAG2):c.22G>A (p.Val8Ile)

CA293055

138885 (ClinVar)

Gene: RAG2

Condition: recombinase activating gene 2 deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: cffb3d84-595d-43bc-89b1-1913bdc71144

Approved on: 2024-01-17

Published on: 2024-01-17

HGVS expressions

NM_000536.4:c.22G>A
NM_000536.4(RAG2):c.22G>A (p.Val8Ile)
NC_000011.10:g.36594147C>T
CM000673.2:g.36594147C>T
NC_000011.9:g.36615697C>T
CM000673.1:g.36615697C>T
NC_000011.8:g.36572273C>T
NG_007573.1:g.9090G>A
NG_033154.1:g.4655C>T
ENST00000311485.8:c.22G>A
ENST00000311485.7:c.22G>A
ENST00000524423.1:n.131+3955G>A
ENST00000527033.5:c.22G>A
ENST00000529083.1:c.22G>A
ENST00000618712.4:c.22G>A
NM_000536.3:c.22G>A
NM_001243785.1:c.22G>A
NM_001243786.1:c.22G>A
NM_001243785.2:c.22G>A
NM_001243786.2:c.22G>A

Likely Benign

• Met criteria codes: BS2_Supporting BS1

• Not Met criteria codes: BA1

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.22G>A variant in RAG2 is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 8 (p.Val8Ile). This variant has a population max filtering allele frequency of 0.004397 in gnomAD, which is above the threshold for BS1 set by the ClinGen SCID VCEP for RAG2 (>0.00195). This variant has not been identified in individuals with SCID, though it has been identified in one individual with CID (PMID: 28769923) who carried a co-occurring variant p.D200H (phase unknown, p.D200H not curated by ClinGen SCID VCEP). In addition, this variant is present in 5 homozygotes in gnomAD (BS2_Supporting). In summary, this variant is classified as a Likely Benign for autosomal recessive SCID based on the ACMG criteria applied: BS1 and BS2_Supporting as specified by the ClinGen SCID VCEP (VCEP specifications version 1).

Met criteria codes

• BS2_Supporting: There are 5 homozygotes reported in gnomADv2.1.1, BS2_Supporting.
• BS1: The highest population frequency in gnomAD is 0.01648 (170/10316 alleles) in the Ashkenazi Jewish population. This is higher than the cutoff for BA1 set by the SCID VCEP for RAG2 (>0.00872). HOWEVER, the popmax allele frequency in gnomAD v2.2.1 is 0.004397 and this is the frequency we are using in our RAG2 specifications, so BA1 is not met. This does, however, meet the VCEP's specifications to apply BS1 (>0.00195). Therefore BS1 is met. In addition, there are 5 homozygotes in gnomAD.

Not Met criteria codes

• BA1: The highest population frequency in gnomAD is 0.01648 (170/10316 alleles) in the Ashkenazi Jewish population. This is higher than the cutoff for BA1 set by the SCID VCEP for RAG2 (>0.00872). HOWEVER, the popmax allele frequency in gnomAD v2.2.1 is 0.004397 and this is the frequency we are using in our RAG2 specifications. Therefore BA1 is not met. In addition, there are 5 homozygotes in gnomAD.