rs786205616
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000536.4(RAG2):c.1403_1406del(p.His468ArgfsTer16) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. H468H) has been classified as Likely benign.
Frequency
Consequence
NM_000536.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAG2 | NM_000536.4 | c.1403_1406del | p.His468ArgfsTer16 | frameshift_variant | 2/2 | ENST00000311485.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAG2 | ENST00000311485.8 | c.1403_1406del | p.His468ArgfsTer16 | frameshift_variant | 2/2 | 1 | NM_000536.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461890Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727246
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Combined immunodeficiency with skin granulomas Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 16, 2023 | - - |
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 | Invitae | Apr 28, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the RAG2 protein in which other variant(s) (p.Glu480*) have been determined to be pathogenic (PMID: 21624848, 29772310). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 191271). This premature translational stop signal has been observed in individual(s) with severe combined deficiency (PMID: 26915675). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His468Argfs*16) in the RAG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 60 amino acid(s) of the RAG2 protein. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at