rs193922573
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP4PM2_SupportingPS3_ModeratePM1PM3
This summary comes from the ClinGen Evidence Repository: The c.1309G>A (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Glutamic Acid by Lysine at amino acid 437 (p.Glu437Lys).The filtering allele frequency (the upper threshold of the 95% CI of 9/63722 alleles) of the c.1309G>A variant in RAG2 is 0.000001910 for European (non-Finnish) chromosomes by gnomAD v.4, which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.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 recombination activity assay showed activity of this variant compared to wildtype RAG2 is 0.9% (SEM 0.2), which is lower than the SCID VCEP threshold (<25%) for PS3_Moderate, meeting this criterion (PS3_Moderate, PMID 29772310).The patient presents: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5 pts + T-B-NK+ lymphocyte subset profile 0.5 pts, total is 1 point, PP4 (PMID:29772310). The same patient is a compound heterozygous for his variant and G35A, a pathogenic variant according to SCID VCEP specifications; 1 point, PM3.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: PM2_Supporting, PM1, PS3_Moderate, PP4, and PM3 (VCEP specifications version 1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA214215/MONDO:0000573/124
Frequency
Consequence
NM_000536.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAG2 | NM_000536.4 | c.1309G>A | p.Glu437Lys | missense_variant | 2/2 | ENST00000311485.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAG2 | ENST00000311485.8 | c.1309G>A | p.Glu437Lys | missense_variant | 2/2 | 1 | NM_000536.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152092Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251446Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135906
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461870Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727242
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152092Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74276
ClinVar
Submissions by phenotype
Combined immunodeficiency with skin granulomas Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 21, 2023 | - - |
Recombinase activating gene 2 deficiency Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen | Apr 01, 2024 | The c.1309G>A (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Glutamic Acid by Lysine at amino acid 437 (p.Glu437Lys). The filtering allele frequency (the upper threshold of the 95% CI of 9/63722 alleles) of the c.1309G>A variant in RAG2 is 0.000001910 for European (non-Finnish) chromosomes by gnomAD v.4, which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD. 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 recombination activity assay showed activity of this variant compared to wildtype RAG2 is 0.9% (SEM 0.2), which is lower than the SCID VCEP threshold (<25%) for PS3_Moderate, meeting this criterion (PS3_Moderate, PMID 29772310). The patient presents: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5 pts + T-B-NK+ lymphocyte subset profile 0.5 pts, total is 1 point, PP4 (PMID: 29772310). The same patient is a compound heterozygous for his variant and G35A, a pathogenic variant according to SCID VCEP specifications; 1 point, PM3. 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: PM2_Supporting, PM1, PS3_Moderate, PP4, and PM3 (VCEP specifications version 1.0). - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 21, 2015 | The E437K variant in the RAG2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E437K variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E437K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in nearby residue (K440N) has been reported in the Human Gene Mutation Database in association with Omenn syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. The E437K variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 10, 2018 | Variant summary: RAG2 c.1309G>A (p.Glu437Lys) results in a conservative amino acid change located in the Recombination activating protein 2 PHD domain (IPR025162) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 246216 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in RAG2 causing Severe Combined Immunodeficiency Syndrome (1.6e-05 vs 7.10e-04), allowing no conclusion about variant significance. The variant, c.1309G>A, has been reported in the literature and an unpublished report in individuals affected with Severe Combined Immunodeficiency Syndrome (Nicholas_2011, Dobbs_2017) as well as in a case of common variable immunodeficiency (CVID) (Yashar_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Inborn error of immunity;CN257931:Recombinase activating gene 2 deficiency;na:Atypical severe combined immunodeficiency due to complete RAG1/2 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Pediatric Immunology Service, The Chaim Sheba Medical Center at Tel HaShomer | Mar 06, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at