11-36593483-C-T

Position:

• chr11-36593483-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM3 PM1_Supporting PS3 PM2_Supporting PP4 PP1

This summary comes from the ClinGen Evidence Repository: The c.686G>A (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of arginine by glycine at amino acid 229 (p.Arg229Gln). The filtering allele frequency (the upper threshold of the 95% CI of 2/113660) of the c.686G>A variant in RAG2 is 0.000002920 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant resides within a region, amino acids 1-383, of RAG2 that is defined as a critical functional domain by the ClinGen SCID VCEP (PMID:26996199) (PM1_Supporting). At least one patient with this variant displayed: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt) + T-B-NK+ lymphocyte subset profile (0.5pt) total 1 pt, which is highly specific for SCID (PP4, PMID:30307608). The variant showed disrupted V(D)J recombination activity at 8.9% of WT-RAG2 (PMID:29772310). Additionally, an animal model homozygous for the variant recapitulates most phenotypes associated with OS (PMID:17476358) (PS3). The variant has been reported to segregate with SCID in 02 affected siblings from one family (Proband + one) (PP1_Supporting; PMID:30307608). Five patients (14–18) were homozygous for the variant (reaching the maximum 1 pt) PM3_Moderate (PMID:30307608).In summary, this variant meets the criteria to be classified as pathogenic for AR SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PP4, PM3_Moderate, PS3, PP1, and PM1_Supporting. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA122854/MONDO:0000573/124

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: RAG2 NM_000536.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7 U:1
• Conservation: PhyloP100: 7.57

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 Pathogenic. Variant got 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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	c.686G>A	p.Arg229Gln	missense_variant	2/2	ENST00000311485.8	NP_000527.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAG2	ENST00000311485.8	c.686G>A	p.Arg229Gln	missense_variant	2/2	1	NM_000536.4	ENSP00000308620	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152028 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251160 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461720 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Histiocytic medullary reticulosis Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2001	- -

Combined immunodeficiency with skin granulomas Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 25, 2024

- -

Recombinase activating gene 2 deficiency Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Nov 14, 2023

The c.686G>A (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of arginine by glycine at amino acid 229 (p.Arg229Gln). The filtering allele frequency (the upper threshold of the 95% CI of 2/113660) of the c.686G>A variant in RAG2 is 0.000002920 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant resides within a region, amino acids 1-383, of RAG2 that is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199) (PM1_Supporting). At least one patient with this variant displayed: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt) + T-B-NK+ lymphocyte subset profile (0.5pt) total 1 pt, which is highly specific for SCID (PP4, PMID: 30307608). The variant showed disrupted V(D)J recombination activity at 8.9% of WT-RAG2 (PMID: 29772310). Additionally, an animal model homozygous for the variant recapitulates most phenotypes associated with OS (PMID: 17476358) (PS3). The variant has been reported to segregate with SCID in 02 affected siblings from one family (Proband + one) (PP1_Supporting; PMID: 30307608). Five patients (14–18) were homozygous for the variant (reaching the maximum 1 pt) PM3_Moderate (PMID: 30307608). In summary, this variant meets the criteria to be classified as pathogenic for AR SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PP4, PM3_Moderate, PS3, PP1, and PM1_Supporting. (VCEP specifications version 1). -

Severe combined immunodeficiency, B cell-negative Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2001

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 229 of the RAG2 protein (p.Arg229Gln). This variant is present in population databases (rs121917894, gnomAD 0.002%). This missense change has been observed in individuals with RAG2-related disease (PMID: 11133745, 11313270, 30307608). ClinVar contains an entry for this variant (Variation ID: 13130). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAG2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RAG2 function (PMID: 8810255, 11313270). This variant disrupts the p.Arg229 amino acid residue in RAG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11133745, 15025726, 16960852, 28747913). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

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

Uncertain significance, criteria provided, single submitter

research

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

Mar 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;H
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.7	D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.83
MVP		0.98
MPC		0.47
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.79
gMVP		0.85

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

Other links and lift over

dbSNP: rs121917894; hg19: chr11-36615033;