rs757913323

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP4PM1PM2_SupportingPM3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1421A>G (NM_000536.4) variant in RAG2 is a missense variant predicted to cause substitution of Asparagine by Serine at amino acid 474 (p.Asn474Ser).The filtering allele frequency (the upper threshold of the 95% CI of 2/30614 alleles) of the c.1421A>G variant in RAG2 is 0.00001082 for South Asian 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). No homozygotes have been observed in gnomAD.This variant is located in the PHD domain, amino acids 414-487 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID:26996199); PM1_Moderate.However, two functional assays published in the literature showed that this variant did not show differences in contrast with wild-type, both in the quantitative assay: The recombination activity assay showed activity of this variant compared to wildtype RAG2 is 97.5% (SEM 5.9), which is higher than the SCID VCEP threshold for Moderate (<25%) or Supporting (25-60%) level of evidence (PMID 29772310) AND in the qualitative assay: The analyses had not yet identified any particular defect associated with the N474S mutation (PMID:20234091); Thus, PS3 is not applied.Diagnostic criteria for SCID (Criterion 1: Very Low T cells <0.05x109/L + Criterion 3 No alternate explanation for low t-cell count AND <20% of CD4+ T cell have naive cell surface markers - based on CD45RA and CD45R0 count) 0.5pts + T-B-NK+ lymphocyte subset profile 0.5pts, the total is 1 point, PP4 is met (PMID:11133745). This patient is homozygous, 0.5 pts, PM3 is met at supporting level.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_Supporting, PM1_Moderate, PP4, and PM3_Supporting (VCEP specifications version 1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5950417/MONDO:0000573/124

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

RAG2
ENST00000311485.8 missense

Scores

2
17

Clinical Significance

Uncertain significance reviewed by expert panel U:3B:1

Conservation

PhyloP100: 0.748
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]
RAG1 (HGNC:9831): (recombination activating 1) The protein encoded by this gene is involved in activation of immunoglobulin V-D-J recombination. The encoded protein is involved in recognition of the DNA substrate, but stable binding and cleavage activity also requires RAG2. Defects in this gene can be the cause of several diseases. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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.
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.1421A>G p.Asn474Ser 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.1421A>G p.Asn474Ser missense_variant 2/21 NM_000536.4 ENSP00000308620 P1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152116
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
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
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251484
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135920
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 SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461888
Hom.:
0
Cov.:
31
AF XY:
0.0000124
AC XY:
9
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000719
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152116
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74300
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000278
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3Benign:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Recombinase activating gene 2 deficiency Uncertain:1
Uncertain significance, reviewed by expert panelcurationClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGenJan 23, 2024The c.1421A>G (NM_000536.4) variant in RAG2 is a missense variant predicted to cause substitution of Asparagine by Serine at amino acid 474 (p.Asn474Ser). The filtering allele frequency (the upper threshold of the 95% CI of 2/30614 alleles) of the c.1421A>G variant in RAG2 is 0.00001082 for South Asian 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). No homozygotes have been observed in gnomAD. This variant is located in the PHD domain, amino acids 414-487 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1_Moderate. However, two functional assays published in the literature showed that this variant did not show differences in contrast with wild-type, both in the quantitative assay: The recombination activity assay showed activity of this variant compared to wildtype RAG2 is 97.5% (SEM 5.9), which is higher than the SCID VCEP threshold for Moderate (<25%) or Supporting (25-60%) level of evidence (PMID 29772310) AND in the qualitative assay: The analyses had not yet identified any particular defect associated with the N474S mutation (PMID: 20234091); Thus, PS3 is not applied. Diagnostic criteria for SCID (Criterion 1: Very Low T cells <0.05x109/L + Criterion 3 No alternate explanation for low t-cell count AND <20% of CD4+ T cell have naive cell surface markers - based on CD45RA and CD45R0 count) 0.5pts + T-B-NK+ lymphocyte subset profile 0.5pts, the total is 1 point, PP4 is met (PMID: 11133745). This patient is homozygous, 0.5 pts, PM3 is met at supporting level. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_Supporting, PM1_Moderate, PP4, and PM3_Supporting (VCEP specifications version 1.0). -
Histiocytic medullary reticulosis Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Feb 19, 2020- -
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 04, 2022This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 474 of the RAG2 protein (p.Asn474Ser). This variant is present in population databases (rs757913323, gnomAD 0.006%). This missense change has been observed in individual(s) with severe combined immunodeficiency (SCID) (PMID: 11133745). ClinVar contains an entry for this variant (Variation ID: 496633). 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 not expected to disrupt RAG2 protein function. Experimental studies have shown that this missense change does not substantially affect RAG2 function (PMID: 20234091, 26692406, 29772310). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Inborn error of immunity;C1832322:Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;CN257931:Recombinase activating gene 2 deficiency Benign:1
Likely benign, criteria provided, single submitterresearchPediatric Immunology Service, The Chaim Sheba Medical Center at Tel HaShomerMar 06, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.061
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
17
DANN
Benign
0.96
DEOGEN2
Benign
0.28
T;T
Eigen
Benign
-0.72
Eigen_PC
Benign
-0.47
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Uncertain
0.88
.;D
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.13
T;T
MetaSVM
Benign
-0.56
T
MutationAssessor
Benign
-0.90
N;N
MutationTaster
Benign
0.99
N
PrimateAI
Benign
0.43
T
PROVEAN
Benign
0.050
N;.
REVEL
Benign
0.26
Sift
Benign
0.80
T;.
Sift4G
Benign
0.75
T;T
Polyphen
0.0
B;B
Vest4
0.046
MutPred
0.78
Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP
0.80
MPC
0.39
ClinPred
0.068
T
GERP RS
1.7
Varity_R
0.020
gMVP
0.10

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: rs757913323; hg19: chr11-36614298; API