rs16929093

chr11-36593291-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000536.4(RAG2):c.878A>G(p.Glu293Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00571 in 1,614,168 control chromosomes in the GnomAD database, including 437 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.030 (234 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (203 hom.)
• Consequence: RAG2 NM_000536.4 missense
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: 3.94

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018733144).
• BP6: Variant 11-36593291-T-C is Benign according to our data. Variant chr11-36593291-T-C is described in ClinVar as [Benign]. Clinvar id is 256378.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAG2	NM_000536.4	c.878A>G	p.Glu293Gly	missense_variant	2/2	ENST00000311485.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAG2	ENST00000311485.8	c.878A>G	p.Glu293Gly	missense_variant	2/2	1	NM_000536.4	P1

Frequencies

GnomAD3 genomes AF: 0.0303 AC: 4607 AN: 152178 Hom.: 234 Cov.: 32

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

GnomAD3 exomes AF: 0.00827 AC: 2079 AN: 251342 Hom.: 92 AF XY: 0.00609 AC XY: 827 AN XY: 135822

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 SAS exome AF: 0.0000980

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.: 31 AF XY: 0.00274 AC XY: 1993 AN XY: 727238

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.00615

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000246

Gnomad4 OTH exome AF: 0.00604

GnomAD4 genome AF: 0.0303 AC: 4615 AN: 152296 Hom.: 234 Cov.: 32 AF XY: 0.0286 AC XY: 2133 AN XY: 74472

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.0121

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00631 Hom.: 94

Bravo AF: 0.0343

ESP6500AA AF: 0.102 AC: 449

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0101 AC: 1225

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

Histiocytic medullary reticulosis Benign:2

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Recombinase activating gene 2 deficiency Benign:1

Benign, reviewed by expert panel

curation

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Apr 03, 2024

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

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of 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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	16
Dann	Benign	0.95
DEOGEN2	Uncertain	0.73	D;D
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.92	D
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	0.63	N
PrimateAI	Benign	0.32	T
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	T
GERP RS		1.7
Varity_R		0.10
gMVP		0.49

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

LitVar

Other links and lift over

dbSNP: rs16929093; hg19: chr11-36614841;