GeneBe

11-36593483-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2_SupportingPM1_SupportingPS3PM3PP4PP1

This summary comes from the ClinGen Evidence Repository: The c.686G>A (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of arginine by glycine at amino acid 229 (p.Arg229Gln). The filtering allele frequency (the upper threshold of the 95% CI of 2/113660) of the c.686G>A variant in RAG2 is 0.000002920 for European (non-Finnish) 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). This variant resides within a region, amino acids 1-383, of RAG2 that is defined as a critical functional domain by the ClinGen SCID VCEP (PMID:26996199) (PM1_Supporting). At least one patient with this variant displayed: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt) + T-B-NK+ lymphocyte subset profile (0.5pt) total 1 pt, which is highly specific for SCID (PP4, PMID:30307608). The variant showed disrupted V(D)J recombination activity at 8.9% of WT-RAG2 (PMID:29772310). Additionally, an animal model homozygous for the variant recapitulates most phenotypes associated with OS (PMID:17476358) (PS3). The variant has been reported to segregate with SCID in 02 affected siblings from one family (Proband + one) (PP1_Supporting; PMID:30307608). Five patients (14–18) were homozygous for the variant (reaching the maximum 1 pt) PM3_Moderate (PMID:30307608).In summary, this variant meets the criteria to be classified as pathogenic for AR SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PP4, PM3_Moderate, PS3, PP1, and PM1_Supporting. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA122854/MONDO:0000573/124

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

RAG2
NM_000536.4 missense

Scores

15
2
2

Clinical Significance

Pathogenic reviewed by expert panel P:8U:1

Conservation

PhyloP100: 7.57

Publications

32 publications found
Variant links:
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]
RAG2 Gene-Disease associations (from GenCC):
  • Omenn syndrome
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
  • recombinase activating gene 2 deficiency
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PS3
For more information check the summary or visit ClinGen Evidence Repository.
PM1
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RAG2NM_000536.4 linkc.686G>A p.Arg229Gln missense_variant Exon 2 of 2 ENST00000311485.8 NP_000527.2 P55895

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RAG2ENST00000311485.8 linkc.686G>A p.Arg229Gln missense_variant Exon 2 of 2 1 NM_000536.4 ENSP00000308620.4 P55895

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152028
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD2 exomes
AF:
0.00000796
AC:
2
AN:
251160
AF XY:
0.00000737
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000198
AC:
29
AN:
1461720
Hom.:
0
Cov.:
31
AF XY:
0.0000124
AC XY:
9
AN XY:
727182
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53256
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000225
AC:
25
AN:
1112002
Other (OTH)
AF:
0.0000497
AC:
3
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.465
Heterozygous variant carriers
0
2
4
5
7
9
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152146
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74360
show subpopulations
African (AFR)
AF:
0.0000723
AC:
3
AN:
41490
American (AMR)
AF:
0.00
AC:
0
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5170
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10588
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68004
Other (OTH)
AF:
0.000473
AC:
1
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.485
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.0000499
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:8Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Histiocytic medullary reticulosis Pathogenic:2
May 01, 2001
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Sep 16, 2020
Natera, Inc.
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Combined immunodeficiency with skin granulomas Pathogenic:1
Mar 25, 2024
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Recombinase activating gene 2 deficiency Pathogenic:1
Nov 14, 2023
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen
Significance:Pathogenic
Review Status:reviewed by expert panel
Collection Method:curation

The c.686G>A (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of arginine by glycine at amino acid 229 (p.Arg229Gln). The filtering allele frequency (the upper threshold of the 95% CI of 2/113660) of the c.686G>A variant in RAG2 is 0.000002920 for European (non-Finnish) 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). This variant resides within a region, amino acids 1-383, of RAG2 that is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199) (PM1_Supporting). At least one patient with this variant displayed: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt) + T-B-NK+ lymphocyte subset profile (0.5pt) total 1 pt, which is highly specific for SCID (PP4, PMID: 30307608). The variant showed disrupted V(D)J recombination activity at 8.9% of WT-RAG2 (PMID: 29772310). Additionally, an animal model homozygous for the variant recapitulates most phenotypes associated with OS (PMID: 17476358) (PS3). The variant has been reported to segregate with SCID in 02 affected siblings from one family (Proband + one) (PP1_Supporting; PMID: 30307608). Five patients (14–18) were homozygous for the variant (reaching the maximum 1 pt) PM3_Moderate (PMID: 30307608). In summary, this variant meets the criteria to be classified as pathogenic for AR SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PP4, PM3_Moderate, PS3, PP1, and PM1_Supporting. (VCEP specifications version 1). -

Severe combined immunodeficiency, B cell-negative Pathogenic:1
May 01, 2001
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas Pathogenic:1
Nov 11, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 229 of the RAG2 protein (p.Arg229Gln). This variant is present in population databases (rs121917894, gnomAD 0.002%). This missense change has been observed in individuals with RAG2-related disease (PMID: 11133745, 11313270, 30307608). ClinVar contains an entry for this variant (Variation ID: 13130). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 8810255, 11313270). This variant disrupts the p.Arg229 amino acid residue in RAG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11133745, 15025726, 16960852, 28747913). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1
Jul 10, 2021
Kariminejad - Najmabadi Pathology & Genetics Center
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas;C2700553:Histiocytic medullary reticulosis Pathogenic:1
May 29, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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 Uncertain:1
Mar 06, 2018
Pediatric Immunology Service, The Chaim Sheba Medical Center at Tel HaShomer
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.57
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.49
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.94
D;D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.96
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
.;D
M_CAP
Pathogenic
0.36
D
MetaRNN
Pathogenic
0.95
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.8
H;H
PhyloP100
7.6
PrimateAI
Benign
0.41
T
PROVEAN
Uncertain
-3.7
D;.
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.83
MVP
0.98
MPC
0.47
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.79
gMVP
0.85
Mutation Taster
=11/89
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs121917894; hg19: chr11-36615033; API