rs193922574

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP4PM3PM2_SupportingPM1_SupportingPM5_Supporting

This summary comes from the ClinGen Evidence Repository: The c.217C>T (NM_000536.4) variant in RAG2 is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 73 (p.Arg73Cys).The filtering allele frequency (the upper threshold of the 95% CI of 2/16256) of the c.217C>T variant in RAG2 is 0.00002132 for African/African American chromosomes by gnomAD v2.1.1 (no homozygous reported), 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).PMID:24481607: Proband compound heterozygous (comp het ( R73C/C178X, Pathogenic according to SCID VCEP specifications, 1 pt, PM3_met).NM_000536.4(RAG2):c.218G>A (p.Arg73His), LP according to SCID VCEP specifications, PM5_Supporting.At least one patient with this variant displayed: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt) and T-B-NK+ lymphocyte subset profile (0.5pt), totalizing 1 pt, which is highly specific for SCID (PP4, PMID:20603253). In summary, this variant is classified as Likely Pathogenic for AR SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PP4, PM1_Supporting, PM3, PM5_Supporting, and PM2_Supporting. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA214218/MONDO:0000573/124

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

RAG2
ENST00000311485.8 missense

Scores

12
6
1

Clinical Significance

Likely pathogenic reviewed by expert panel P:6

Conservation

PhyloP100: 6.41
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

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.
PM5
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/exons MANE Protein UniProt
RAG2NM_000536.4 linkuse as main transcriptc.217C>T p.Arg73Cys missense_variant 2/2 ENST00000311485.8 NP_000527.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RAG2ENST00000311485.8 linkuse as main transcriptc.217C>T p.Arg73Cys missense_variant 2/21 NM_000536.4 ENSP00000308620 P1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152230
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251454
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135896
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000404
AC:
59
AN:
1461866
Hom.:
0
Cov.:
31
AF XY:
0.0000358
AC XY:
26
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000504
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152230
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000378
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:6
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Recombinase activating gene 2 deficiency Pathogenic:2
Likely pathogenic, reviewed by expert panelcurationClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGenNov 14, 2023The c.217C>T (NM_000536.4) variant in RAG2 is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 73 (p.Arg73Cys). The filtering allele frequency (the upper threshold of the 95% CI of 2/16256) of the c.217C>T variant in RAG2 is 0.00002132 for African/African American chromosomes by gnomAD v2.1.1 (no homozygous reported), 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). PMID: 24481607: Proband compound heterozygous (comp het ( R73C/C178X, Pathogenic according to SCID VCEP specifications, 1 pt, PM3_met). NM_000536.4(RAG2):c.218G>A (p.Arg73His), LP according to SCID VCEP specifications, PM5_Supporting. At least one patient with this variant displayed: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt) and T-B-NK+ lymphocyte subset profile (0.5pt), totalizing 1 pt, which is highly specific for SCID (PP4, PMID: 20603253). In summary, this variant is classified as Likely Pathogenic for AR SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PP4, PM1_Supporting, PM3, PM5_Supporting, and PM2_Supporting. (VCEP specifications version 1). -
Pathogenic, criteria provided, single submitterclinical testingIntergen, Intergen Genetics and Rare Diseases Diagnosis CenterAug 31, 2023- -
Combined immunodeficiency with skin granulomas Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 15, 2024- -
Severe combined immunodeficiency disease Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 03, 2021Variant summary: RAG2 c.217C>T (p.Arg73Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251454 control chromosomes. c.217C>T has been reported in the literature in individuals affected with Severe Combined Immunodeficiency Syndrome (e.g. Adeli_2010, Pasic_2014, Dvorak_2014, Bai_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, citing the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Histiocytic medullary reticulosis Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingNatera, Inc.Aug 04, 2020- -
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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 09, 2023This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 73 of the RAG2 protein (p.Arg73Cys). This variant is present in population databases (rs193922574, gnomAD 0.01%). This missense change has been observed in individuals with severe combined immunodeficiency (SCID) (PMID: 20603253, 24481607, 26476733; Invitae). This variant is also known as c.811C>T. ClinVar contains an entry for this variant (Variation ID: 36719). 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. This variant disrupts the p.Arg73 amino acid residue in RAG2. Other variant(s) that disrupt this residue have been observed in individuals with RAG2-related conditions (PMID: 21131235, 26515615, 28747913), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.72
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.49
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.90
D;D;.
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.96
.;D;D
M_CAP
Pathogenic
0.35
D
MetaRNN
Pathogenic
0.98
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.5
H;H;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-5.7
D;.;D
REVEL
Pathogenic
0.95
Sift
Uncertain
0.011
D;.;D
Sift4G
Uncertain
0.0080
D;D;.
Polyphen
1.0
D;D;.
Vest4
0.84
MutPred
0.92
Loss of phosphorylation at Y68 (P = 0.1194);Loss of phosphorylation at Y68 (P = 0.1194);Loss of phosphorylation at Y68 (P = 0.1194);
MVP
0.97
MPC
0.11
ClinPred
0.93
D
GERP RS
5.8
Varity_R
0.39
gMVP
0.85

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs193922574; hg19: chr11-36615502; COSMIC: COSV57558393; COSMIC: COSV57558393; API