chr11-36593291-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.878A>G (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Glutamic Acid by Glycine at amino acid 293 (p.Glu293Gly).The filtering allele frequency (the lower threshold of the 95% CI of 7999/75012 alleles) of the c.878A>G variant in RAG2 is 0.1047 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1, and therefore meets this criterion (BA1).Additionally, 437 adult homozygous occurrences are reported in gnomAD v4 (BS2_Supporting)In summary, this variant meets the criteria to be classified as Benign for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA5950510/MONDO:0000573/124

Frequency

Genomes: 𝑓 0.030 ( 234 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 203 hom. )

Consequence

RAG2
NM_000536.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:9

Conservation

PhyloP100: 3.94

Publications

12 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 links:

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]

RAG1 Gene-Disease associations (from GenCC):

immunodeficiency disease
Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
Omenn syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Genomics England PanelApp, Ambry Genetics
recombinase activating gene 1 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
combined immunodeficiency due to partial RAG1 deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RAG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAG2	NM_000536.4 link	c.878A>G	p.Glu293Gly	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
RAG2	ENST00000311485.8 link	c.878A>G	p.Glu293Gly	missense_variant	Exon 2 of 2	1	NM_000536.4	ENSP00000308620.4		P55895

Frequencies

GnomAD3 genomes

AF:

0.0303

AC:

4607

AN:

152178

Hom.:

234

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0121

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.0181

GnomAD2 exomes

AF:

0.00827

AC:

2079

AN:

251342

AF XY:

0.00609

show subpopulations

Gnomad AFR exome

AF:

0.110

Gnomad AMR exome

AF:

0.00555

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000502

Gnomad OTH exome

AF:

0.00538

GnomAD4 exome

AF:

0.00315

AC:

4607

AN:

1461872

Hom.:

203

Cov.:

AF XY:

0.00274

AC XY:

1993

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.109

AC:

3637

AN:

33476

American (AMR)

AF:

0.00615

AC:

275

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000936

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00624

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000246

AC:

273

AN:

1111998

Other (OTH)

AF:

0.00604

AC:

365

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

315

630

946

1261

1576

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<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:

0.0303

AC:

4615

AN:

152296

Hom.:

234

Cov.:

AF XY:

0.0286

AC XY:

2133

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.105

AC:

4362

AN:

41536

American (AMR)

AF:

0.0121

AC:

185

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000829

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68030

Other (OTH)

AF:

0.0180

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

205

410

615

820

1025

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00927

Hom.:

165

Bravo

AF:

0.0343

ESP6500AA

AF:

0.102

AC:

449

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0101

AC:

1225

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Histiocytic medullary reticulosis

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Recombinase activating gene 2 deficiency

Benign:1

Apr 03, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.878A>G (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Glutamic Acid by Glycine at amino acid 293 (p.Glu293Gly). The filtering allele frequency (the lower threshold of the 95% CI of 7999/75012 alleles) of the c.878A>G variant in RAG2 is 0.1047 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1, and therefore meets this criterion (BA1). Additionally, 437 adult homozygous occurrences are reported in gnomAD v4 (BS2_Supporting) In summary, this variant meets the criteria to be classified as Benign for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1) -

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.73

D;D

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.51

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.82

.;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.8

L;L

PhyloP100

3.9

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.6

D;.

REVEL

Benign

0.18

Sift

Benign

0.079

T;.

Sift4G

Benign

0.067

T;T

Polyphen

0.0

B;B

Vest4

0.065

MPC

0.090

ClinPred

0.030

GERP RS

1.7

Varity_R

0.10

gMVP

0.49

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over