rs757913323
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP4PM1PM2_SupportingPM3_Supporting
This summary comes from the ClinGen Evidence Repository: The c.1421A>G (NM_000536.4) variant in RAG2 is a missense variant predicted to cause substitution of Asparagine by Serine at amino acid 474 (p.Asn474Ser).The filtering allele frequency (the upper threshold of the 95% CI of 2/30614 alleles) of the c.1421A>G variant in RAG2 is 0.00001082 for South Asian chromosomes by gnomAD v2.1.1, 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_Moderate.However, two functional assays published in the literature showed that this variant did not show differences in contrast with wild-type, both in the quantitative assay: The recombination activity assay showed activity of this variant compared to wildtype RAG2 is 97.5% (SEM 5.9), which is higher than the SCID VCEP threshold for Moderate (<25%) or Supporting (25-60%) level of evidence (PMID 29772310) AND in the qualitative assay: The analyses had not yet identified any particular defect associated with the N474S mutation (PMID:20234091); Thus, PS3 is not applied.Diagnostic criteria for SCID (Criterion 1: Very Low T cells <0.05x109/L + Criterion 3 No alternate explanation for low t-cell count AND <20% of CD4+ T cell have naive cell surface markers - based on CD45RA and CD45R0 count) 0.5pts + T-B-NK+ lymphocyte subset profile 0.5pts, the total is 1 point, PP4 is met (PMID:11133745). This patient is homozygous, 0.5 pts, PM3 is met at supporting level.In summary, this variant meets the criteria to be classified as a variant of uncertain significance 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_Moderate, PP4, and PM3_Supporting (VCEP specifications version 1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5950417/MONDO:0000573/124
Frequency
Consequence
ENST00000311485.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RAG2 | NM_000536.4 | c.1421A>G | p.Asn474Ser | missense_variant | 2/2 | ENST00000311485.8 | NP_000527.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RAG2 | ENST00000311485.8 | c.1421A>G | p.Asn474Ser | missense_variant | 2/2 | 1 | NM_000536.4 | ENSP00000308620 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152116Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251484Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135920
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727244
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152116Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74300
ClinVar
Submissions by phenotype
Recombinase activating gene 2 deficiency Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen | Jan 23, 2024 | The c.1421A>G (NM_000536.4) variant in RAG2 is a missense variant predicted to cause substitution of Asparagine by Serine at amino acid 474 (p.Asn474Ser). The filtering allele frequency (the upper threshold of the 95% CI of 2/30614 alleles) of the c.1421A>G variant in RAG2 is 0.00001082 for South Asian chromosomes by gnomAD v2.1.1, 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_Moderate. However, two functional assays published in the literature showed that this variant did not show differences in contrast with wild-type, both in the quantitative assay: The recombination activity assay showed activity of this variant compared to wildtype RAG2 is 97.5% (SEM 5.9), which is higher than the SCID VCEP threshold for Moderate (<25%) or Supporting (25-60%) level of evidence (PMID 29772310) AND in the qualitative assay: The analyses had not yet identified any particular defect associated with the N474S mutation (PMID: 20234091); Thus, PS3 is not applied. Diagnostic criteria for SCID (Criterion 1: Very Low T cells <0.05x109/L + Criterion 3 No alternate explanation for low t-cell count AND <20% of CD4+ T cell have naive cell surface markers - based on CD45RA and CD45R0 count) 0.5pts + T-B-NK+ lymphocyte subset profile 0.5pts, the total is 1 point, PP4 is met (PMID: 11133745). This patient is homozygous, 0.5 pts, PM3 is met at supporting level. In summary, this variant meets the criteria to be classified as a variant of uncertain significance 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_Moderate, PP4, and PM3_Supporting (VCEP specifications version 1.0). - |
Histiocytic medullary reticulosis Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 19, 2020 | - - |
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 04, 2022 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 474 of the RAG2 protein (p.Asn474Ser). This variant is present in population databases (rs757913323, gnomAD 0.006%). This missense change has been observed in individual(s) with severe combined immunodeficiency (SCID) (PMID: 11133745). ClinVar contains an entry for this variant (Variation ID: 496633). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAG2 protein function. Experimental studies have shown that this missense change does not substantially affect RAG2 function (PMID: 20234091, 26692406, 29772310). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Inborn error of immunity;C1832322:Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;CN257931:Recombinase activating gene 2 deficiency Benign:1
Likely benign, 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