rs150762709

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS2_SupportingBS1

This summary comes from the ClinGen Evidence Repository: The NM_000536.4:c.22G>A variant in RAG2 is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 8 (p.Val8Ile). This variant has a population max filtering allele frequency of 0.004397 in gnomAD, which is above the threshold for BS1 set by the ClinGen SCID VCEP for RAG2 (>0.00195). This variant has not been identified in individuals with SCID, though it has been identified in one individual with CID (PMID:28769923) who carried a co-occurring variant p.D200H (phase unknown, p.D200H not curated by ClinGen SCID VCEP). In addition, this variant is present in 5 homozygotes in gnomAD (BS2_Supporting). In summary, this variant is classified as a Likely Benign for autosomal recessive SCID based on the ACMG criteria applied: BS1 and BS2_Supporting as specified by the ClinGen SCID VCEP (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA293055/MONDO:0000573/124

Frequency

Genomes: 𝑓 0.0031 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 21 hom. )

Consequence

RAG2
NM_000536.4 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel B:12

Conservation

PhyloP100: 1.29

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:

IFTAP (HGNC:25142): (intraflagellar transport associated protein) This gene encodes a protein that was identified as a cellular interacting partner of non-structural protein 10 of the severe acute respiratory syndrome coronavirus (SARS-CoV). The encoded protein may function as a negative regulator of transcription. There is a pseudogene for this gene on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]

IFTAP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BS1

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

BS2

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.22G>A	p.Val8Ile	missense_variant	Exon 2 of 2	ENST00000311485.8	NP_000527.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAG2	ENST00000311485.8 link	c.22G>A	p.Val8Ile	missense_variant	Exon 2 of 2	1	NM_000536.4	ENSP00000308620.4

Frequencies

GnomAD3 genomes

AF:

0.00306

AC:

465

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00445

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00351

AC:

873

AN:

248640

AF XY:

0.00345

show subpopulations

Gnomad AFR exome

AF:

0.000463

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.0167

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00277

Gnomad NFE exome

AF:

0.00473

Gnomad OTH exome

AF:

0.00413

GnomAD4 exome

AF:

0.00458

AC:

6689

AN:

1459636

Hom.:

Cov.:

AF XY:

0.00448

AC XY:

3253

AN XY:

726320

show subpopulations

African (AFR)

AF:

0.000658

AC:

AN:

33410

American (AMR)

AF:

0.00116

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0162

AC:

423

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00160

AC:

138

AN:

86210

European-Finnish (FIN)

AF:

0.00272

AC:

145

AN:

53332

Middle Eastern (MID)

AF:

0.00677

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00501

AC:

5564

AN:

1110048

Other (OTH)

AF:

0.00507

AC:

306

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

309

618

927

1236

1545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

222

444

666

888

1110

<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:

0.00306

AC:

466

AN:

152318

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

198

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000601

AC:

AN:

41566

American (AMR)

AF:

0.00242

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0167

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00186

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00235

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00445

AC:

303

AN:

68018

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00451

Hom.:

Bravo

AF:

0.00291

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00313

AC:

380

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00387

EpiControl

AF:

0.00397

ClinVar

Significance: Likely benign

Submissions summary: Benign:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:5

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RAG2: BS2 -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Histiocytic medullary reticulosis

Benign:3

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

May 18, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Recombinase activating gene 2 deficiency

Benign:1

Nov 14, 2023

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000536.4:c.22G>A variant in RAG2 is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 8 (p.Val8Ile). This variant has a population max filtering allele frequency of 0.004397 in gnomAD, which is above the threshold for BS1 set by the ClinGen SCID VCEP for RAG2 (>0.00195). This variant has not been identified in individuals with SCID, though it has been identified in one individual with CID (PMID: 28769923) who carried a co-occurring variant p.D200H (phase unknown, p.D200H not curated by ClinGen SCID VCEP). In addition, this variant is present in 5 homozygotes in gnomAD (BS2_Supporting). In summary, this variant is classified as a Likely Benign for autosomal recessive SCID based on the ACMG criteria applied: BS1 and BS2_Supporting as specified by the ClinGen SCID VCEP (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:Likely 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 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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;C2700553:Histiocytic medullary reticulosis

Benign:1

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T;.;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.057

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.61

.;T;T;T

M_CAP

Benign

0.047

MetaRNN

Benign

0.0070

T;T;T;T

MetaSVM

Uncertain

-0.035

MutationAssessor

Benign

1.4

L;L;.;.

PhyloP100

1.3

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.030

N;.;N;N

REVEL

Benign

0.17

Sift

Benign

0.12

T;.;T;T

Sift4G

Benign

0.14

T;T;.;.

Polyphen

0.0010

B;B;.;.

Vest4

0.079

MVP

0.88

MPC

0.31

ClinPred

0.010

GERP RS

4.8

PromoterAI

-0.013

Neutral

(source)

Varity_R

0.058

gMVP

0.096

Mutation Taster

=97/3

polymorphism

(source)

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

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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