The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]


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
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Likely Benign

Met criteria codes 2
BS2_Supporting BS1
Not Met criteria codes 1
BA1

Evidence Links 0

Expert Panel

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
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.
Curation History
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