rs35691292

Variant names:

• chr11-36593525-G-A
• rs35691292
• NM_000536.4:c.644C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-36593525-G-A
• chr11-36593525-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.644C>T (NM_000536.4) variant in RAG2 is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid 215 (p.Thr215Ile).The filtering allele frequency (the lower threshold of the 95% CI of 2177/91084 alleles) of the c.644C>T variant in RAG2 is 0.02308 for South Asian chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1, and therefore meets this criterion (BA1). Additionally, 42 homozygous individuals have been described (40 and 2 individuals in South Asian and "Remaining" populations, respectively (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. Criteria applied: BA1 and BS2_Supporting (VCEP specifications version 1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA122864/MONDO:0000573/124

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (41 hom.)
• Consequence: RAG2 NM_000536.4 missense
• Clinical Significance: Benign reviewed by expert panel P:1 U:1 B:10
• Conservation: PhyloP100: 5.85
• Publications: 22 publications found

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 Gene-Disease associations (from GenCC):

• Omenn syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
• recombinase activating gene 2 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: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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	c.644C>T	p.Thr215Ile	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	c.644C>T	p.Thr215Ile	missense_variant	Exon 2 of 2	1	NM_000536.4	ENSP00000308620.4

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152162 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00329 AC: 826 AN: 251378 AF XY: 0.00420

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00160 AC: 2339 AN: 1461862 Hom.: 41 Cov.: 31 AF XY: 0.00225 AC XY: 1634 AN XY: 727228

African (AFR) AF: 0.00125 AC: 42 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39700

South Asian (SAS) AF: 0.0239 AC: 2065 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1112004

Other (OTH) AF: 0.00240 AC: 145 AN: 60396

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.00142 AC XY: 106 AN XY: 74454

African (AFR) AF: 0.00123 AC: 51 AN: 41550

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5190

South Asian (SAS) AF: 0.0232 AC: 112 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000463 Hom.: 0

Bravo AF: 0.000472

ExAC AF: 0.00358 AC: 434

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:10

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 23, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 21, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RAG2 c.644C>T (p.Thr215Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. However, these predictions have yet to be functionally assessed. The variant allele was found at a frequency of 0.003 in 277112 control chromosomes in the gnomAD database, including 11 homozygotes. The observed variant frequency is approximately 4.22 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAG2 causing Severe Combined Immunodeficiency Syndrome/Omenn Syndrome phenotype (0.00071), strongly suggesting that the variant is benign. The variant, c.644C>T, has been reported in the literature in individuals affected with Severe Combined Immunodeficiency Syndrome/Omenn Syndrome (Tabori_2004, Lev_2012, Meshaal_2015). These reports do not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency Syndrome/Omenn Syndrome. A ClinVar Submission from a clinical diagnostic laboratory (evaluation after 2014) classifies the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive Benign:2

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of autosomal recessive B cell-negative severe combined immunodeficiency (MIM#614074). (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Histiocytic medullary reticulosis Benign:2

Apr 13, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Severe combined immunodeficiency, B cell-negative Pathogenic:1

Apr 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn error of immunity;C1832322:Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2700553:Histiocytic medullary reticulosis;CN257931:Recombinase activating gene 2 deficiency Uncertain:1

Mar 06, 2018

Pediatric Immunology Service, The Chaim Sheba Medical Center at Tel HaShomer

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Recombinase activating gene 2 deficiency Benign:1

Jan 23, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.644C>T (NM_000536.4) variant in RAG2 is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid 215 (p.Thr215Ile). The filtering allele frequency (the lower threshold of the 95% CI of 2177/91084 alleles) of the c.644C>T variant in RAG2 is 0.02308 for South Asian chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1, and therefore meets this criterion (BA1). Additionally, 42 homozygous individuals have been described (40 and 2 individuals in South Asian and "Remaining" populations, respectively (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. Criteria applied: BA1 and BS2_Supporting (VCEP specifications version 1.0). -

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	.;D
MetaRNN	Benign	0.013	T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.3	M;M
PhyloP100		5.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.048	D;D
Polyphen		0.51	P;P
Vest4		0.93
MVP		0.89
MPC		0.28
ClinPred		0.074	T
GERP RS		5.7
Varity_R		0.48
gMVP		0.56
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs35691292; hg19: chr11-36615075;