11-36593574-C-A
Position:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000536.4(RAG2):c.595G>T(p.Glu199Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,038 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 Pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
RAG2
NM_000536.4 stop_gained
NM_000536.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 7.57
Genes affected
RAG2 (HGNC:9832): (recombination activating 2) This gene encodes a protein that is involved in the initiation of V(D)J recombination during B and T cell development. This protein forms a complex with the product of the adjacent recombination activating gene 1, and this complex can form double-strand breaks by cleaving DNA at conserved recombination signal sequences. The recombination activating gene 1 component is thought to contain most of the catalytic activity, while the N-terminal of the recombination activating gene 2 component is thought to form a six-bladed propeller in the active core that serves as a binding scaffold for the tight association of the complex with DNA. A C-terminal plant homeodomain finger-like motif in this protein is necessary for interactions with chromatin components, specifically with histone H3 that is trimethylated at lysine 4. Mutations in this gene cause Omenn syndrome, a form of severe combined immunodeficiency associated with autoimmune-like symptoms. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 55 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-36593574-C-A is Pathogenic according to our data. Variant chr11-36593574-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 463972.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAG2 | NM_000536.4 | c.595G>T | p.Glu199Ter | stop_gained | 2/2 | ENST00000311485.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAG2 | ENST00000311485.8 | c.595G>T | p.Glu199Ter | stop_gained | 2/2 | 1 | NM_000536.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
1
AN:
152168
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251442Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135884
GnomAD3 exomes
AF:
AC:
3
AN:
251442
Hom.:
AF XY:
AC XY:
2
AN XY:
135884
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461870Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727236
GnomAD4 exome
AF:
AC:
5
AN:
1461870
Hom.:
Cov.:
31
AF XY:
AC XY:
2
AN XY:
727236
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74348
GnomAD4 genome
AF:
AC:
1
AN:
152168
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74348
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
ExAC
AF:
AC:
2
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Histiocytic medullary reticulosis Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 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 | Invitae | Apr 01, 2022 | 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: 463972). This variant has not been reported in the literature in individuals affected with RAG2-related conditions. This variant is present in population databases (rs748727021, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Glu199*) in the RAG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 329 amino acid(s) of the RAG2 protein. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at