11-36593886-C-T

Variant names:

• chr11-36593886-C-T
• rs36001797
• NM_000536.4:c.283G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP4 PM2_Supporting PS3_Moderate PM3 PM1_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000536.4:c.283G>A variant in RAG2 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 95 (p.Gly94Arg). This variant has a population max filtering allele frequency of 0.000007010, which is below the threshold for PM2_Supporting set by the ClinGen SCID VCEP for RAG2 (<0.0000588). This variant is located in the core domain (amino acids 1-383) of RAG2, which is defined as a mutational hotspot/critical functional domain by the ClinGen SCID VCEP (PMID:26996199) (PM1_Supporting). In experimental studies, this variant demonstrates a mean recombination activity that is 0.3% of wildtype, which is below the threshold outlined by the ClinGen SCID VCEP (< 25% of wildtype activity) for PS3_Moderate. This variant has been reported in several individuals with severe combined immunodeficiency or Omenn syndrome. Two unrelated individuals are homozygous for this variant (PMID:33599911, 30307608) (0.5p + 0.5p). Three individuals carry this variant along with a second co-occurring RAG2 variant (p.Trp453Arg (phase unknown, 0.25p), p.Glu480* (phase unknown, 0p), p.Arg229Trp (confirmed in trans, 0p)) (PMID:10891502, 31838659, 15025726). (0.5p + 0.5p +0.25p = 1.25p, PS3). The p.Trp453Arg variant has been classified as Likely Pathogenic, whereas the p.Glu480* and p.Arg229Trp variants have not yet been classified by the ClinGen SCID VCEP. At least one of these reported patients meets PP4 criteria established by the ClinGen SCID VCEP: T-B-NK+ lymphocyte subset profile (0.5p), meets clinical diagnostic criteria for SCID (0.5p), testing via large SCID panel or exome sequencing (0.5p): 1.5p (PMID:33599911). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG criteria applied: PM1_Supporting, PM2_Supporting, PS3_Moderate, PP4, and PM3 as specified by the ClinGen SCID VCEP (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA122861/MONDO:0000573/124

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: RAG2 NM_000536.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:8
• 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 Likely_pathogenic. Variant got 7 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.
• PP4: 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.283G>A	p.Gly95Arg	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.283G>A	p.Gly95Arg	missense_variant	Exon 2 of 2	1	NM_000536.4	ENSP00000308620.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251454 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000770 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Histiocytic medullary reticulosis Pathogenic:3

Nov 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 11, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RAG2 c.283G>A (p.Gly95Arg) results in a non-conservative amino acid change located in the kelch motif in the enzymatically active core (Geier_2015) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-05 in 246230 control chromosomes (gnomAD). c.283G>A has been reported in the literature in multiple individuals affected with Severe Combined Immunodeficiency Syndrome/Omenn Syndrome (Gomez_2000, Tabori_2004, Galal_2018, Geier_2015, Tirosh_2019). These data indicate that the variant is very likely to be associated with disease. A functional study, Gomez_2000, found the variant to impair the ability to mediate the initial nucleolytic steps of the V(D)J recombination reaction, while Tirosh_2019 found the variant to almost completely abolish recombinase activity. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Combined immunodeficiency with skin granulomas Pathogenic:1

Mar 14, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Recombinase activating gene 2 deficiency Pathogenic:1

Nov 14, 2023

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000536.4:c.283G>A variant in RAG2 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 95 (p.Gly94Arg). This variant has a population max filtering allele frequency of 0.000007010, which is below the threshold for PM2_Supporting set by the ClinGen SCID VCEP for RAG2 (<0.0000588). This variant is located in the core domain (amino acids 1-383) of RAG2, which is defined as a mutational hotspot/critical functional domain by the ClinGen SCID VCEP (PMID: 26996199) (PM1_Supporting). In experimental studies, this variant demonstrates a mean recombination activity that is 0.3% of wildtype, which is below the threshold outlined by the ClinGen SCID VCEP (< 25% of wildtype activity) for PS3_Moderate. This variant has been reported in several individuals with severe combined immunodeficiency or Omenn syndrome. Two unrelated individuals are homozygous for this variant (PMID: 33599911, 30307608) (0.5p + 0.5p). Three individuals carry this variant along with a second co-occurring RAG2 variant (p.Trp453Arg (phase unknown, 0.25p), p.Glu480* (phase unknown, 0p), p.Arg229Trp (confirmed in trans, 0p)) (PMID: 10891502, 31838659, 15025726). (0.5p + 0.5p +0.25p = 1.25p, PS3). The p.Trp453Arg variant has been classified as Likely Pathogenic, whereas the p.Glu480* and p.Arg229Trp variants have not yet been classified by the ClinGen SCID VCEP. At least one of these reported patients meets PP4 criteria established by the ClinGen SCID VCEP: T-B-NK+ lymphocyte subset profile (0.5p), meets clinical diagnostic criteria for SCID (0.5p), testing via large SCID panel or exome sequencing (0.5p): 1.5p (PMID: 33599911). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG criteria applied: PM1_Supporting, PM2_Supporting, PS3_Moderate, PP4, and PM3 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;C2673536:Combined immunodeficiency with skin granulomas Pathogenic:1

Jun 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 95 of the RAG2 protein (p.Gly95Arg). This variant is present in population databases (rs36001797, gnomAD 0.05%). This missense change has been observed in individual(s) with Omenn’s syndrome and primary immunodeficiency (PMID: 10891502, 15025726, 26186701). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 13133). 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: 10891502). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Jan 10, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect as G95R almost abolishes recombination activity as compared to the wild-type (PMID: 29772310); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30307608, 31589614, 15025726, 32135276, 31838659, 33599911, 10891502, 26186701, 29772310, 26996199, 27825771, 35482138) -

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas;C2700553:Histiocytic medullary reticulosis Pathogenic:1

Dec 01, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H;H;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-7.0	D;.;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.94
MutPred		0.96		Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);
MVP		0.98
MPC		0.48
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.91
gMVP		0.94

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: rs36001797; hg19: chr11-36615436;