rs16929093

Variant names:

• chr11-36593291-T-C
• rs16929093
• NM_000536.4:c.878A>G

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.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
• Clinical Significance: Benign reviewed by expert panel B:10
• Conservation: PhyloP100: 3.94
• Publications: 12 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]

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: Genomics England PanelApp, G2P, Ambry Genetics, Orphanet
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• combined immunodeficiency due to partial RAG1 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for RAG2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000536.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAG2	NM_000536.4	MANE Select	c.878A>G	p.Glu293Gly	missense	Exon 2 of 2	NP_000527.2	P55895
	RAG2	NM_001243785.2		c.878A>G	p.Glu293Gly	missense	Exon 3 of 3	NP_001230714.1	P55895
	RAG2	NM_001243786.2		c.878A>G	p.Glu293Gly	missense	Exon 3 of 3	NP_001230715.1	P55895

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAG2	ENST00000311485.8	TSL:1 MANE Select	c.878A>G	p.Glu293Gly	missense	Exon 2 of 2	ENSP00000308620.4	P55895
	RAG2	ENST00000527033.6	TSL:4	c.878A>G	p.Glu293Gly	missense	Exon 3 of 3	ENSP00000436895.2	P55895
	RAG2	ENST00000529083.2	TSL:3	c.878A>G	p.Glu293Gly	missense	Exon 2 of 2	ENSP00000436327.2	P55895

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

GnomAD2 exomes AF: 0.00827 AC: 2079 AN: 251342 AF XY: 0.00609

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

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: 6 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86258

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53416

Middle Eastern (MID) AF: 0.00624 AC: 36 AN: 5768

European-Non Finnish (NFE) AF: 0.000246 AC: 273 AN: 1111998

Other (OTH) AF: 0.00604 AC: 365 AN: 60396

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

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: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10630

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68030

Other (OTH) AF: 0.0180 AC: 38 AN: 2116

Alfa AF: 0.00927 Hom.: 165

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

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Histiocytic medullary reticulosis (2)
-	-	2	not specified (2)
-	-	1	Recombinase activating gene 2 deficiency (1)
-	-	1	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (1)
-	-	1	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.9
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.18
Sift	Benign	0.079	T
Sift4G	Benign	0.067	T
Polyphen		0.0	B
Vest4		0.065
MPC		0.090
ClinPred		0.030	T
GERP RS		1.7
Varity_R		0.10
gMVP		0.49
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16929093; hg19: chr11-36614841;