rs148508754
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The ENST00000311485.8(RAG2):c.104G>T(p.Gly35Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G35A) has been classified as Pathogenic.
Frequency
Consequence
ENST00000311485.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RAG2 | NM_000536.4 | c.104G>T | p.Gly35Val | 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.104G>T | p.Gly35Val | missense_variant | 2/2 | 1 | NM_000536.4 | ENSP00000308620 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251316Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135832
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461778Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727188
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74320
ClinVar
Submissions by phenotype
Combined immunodeficiency with skin granulomas Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 14, 2023 | - - |
Inborn error of immunity;C1832322:Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2700553:Histiocytic medullary reticulosis;CN257931:Recombinase activating gene 2 deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Pediatric Immunology Service, The Chaim Sheba Medical Center at Tel HaShomer | Mar 06, 2018 | - - |
Histiocytic medullary reticulosis Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 02, 2021 | - - |
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 06, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 35 of the RAG2 protein (p.Gly35Val). This variant is present in population databases (no rsID available, gnomAD no frequency). This missense change has been observed in individuals with RAG2-related conditions (PMID: 15025726, 30307608). ClinVar contains an entry for this variant (Variation ID: 496618). 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 expected to disrupt RAG2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RAG2 function (PMID: 10777560). For these reasons, this variant has been classified as Pathogenic. - |
RAG2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 10, 2023 | The RAG2 c.104G>T variant is predicted to result in the amino acid substitution p.Gly35Val. This variant has been reported in multiple homozygous individuals with severe combined immunodeficiency (Corneo et al. 2000. PubMed ID: 10777560; Tabori et al. 2004. PubMed ID: 15025726; Meshaal et al. 2018. PubMed ID: 30307608). An in vitro experimental study suggests this variant disrupts the V-D-J recombination process for proper immunological function (Corneo et al. 2000. PubMed ID: 10777560). This variant is reported in one out of 251,316 total alleles in gnomAD (http://gnomad.broadinstitute.org/variant/11-36615615-C-A). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at