rs150762709

Positions:

chr11-36594147-C-T

Variant summary

Our verdict is Likely benign. Variant got -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:11

Conservation

PhyloP100: 1.29

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -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/exons	MANE	Protein	UniProt
RAG2	NM_000536.4 link	c.22G>A	p.Val8Ile	missense_variant	2/2	ENST00000311485.8	NP_000527.2	P55895

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAG2	ENST00000311485.8 link	c.22G>A	p.Val8Ile	missense_variant	2/2	1	NM_000536.4	ENSP00000308620.4		P55895

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

GnomAD3 exomes

AF:

0.00351

AC:

873

AN:

248640

Hom.:

AF XY:

0.00345

AC XY:

466

AN XY:

135074

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 SAS exome

AF:

0.00157

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

Gnomad4 AFR exome

AF:

0.000658

Gnomad4 AMR exome

AF:

0.00116

Gnomad4 ASJ exome

AF:

0.0162

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00160

Gnomad4 FIN exome

AF:

0.00272

Gnomad4 NFE exome

AF:

0.00501

Gnomad4 OTH exome

AF:

0.00507

GnomAD4 genome

AF:

0.00306

AC:

466

AN:

152318

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

198

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000601

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.0167

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.00235

Gnomad4 NFE

AF:

0.00445

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00493

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:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	RAG2: BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Histiocytic medullary reticulosis

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Recombinase activating gene 2 deficiency

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Nov 14, 2023

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

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

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;.;.

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

Varity_R

0.058

gMVP

0.096

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over