rs193922572

Positions:

chr11-36592922-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM3PP4PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1247G>T (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Tryptophan by Leucine at amino acid 416 (p.Trp416Leu).The Popmax Filtering AF (95% confidence) in gnomAD v.4 is 0.0002998, based on 36/91078 alleles in the South Asian population. PM2_Supporting (<0.0000588), BS1 (>0.00195), and BA1 (>0.00872) are not met. No homozygotes have been observed in gnomAD (BS2 is not met).This variant is located in the PHD domain, amino acids 414-487 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID:26996199); PM1.The variant was found in at least four individuals in the literature, with diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met. All of them are homozygous, reaching 1 point for homozygous occurrence. PM3_Moderate (PMID:17572155). Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5pts + T-B-NK+ lymphocyte subset profile 0.5pts; the total is 1 point, PP4 is met (PMID:29772310).The recombination activity assay showed activity of this variant compared to wildtype RAG2 is 1.4% (SEM 0.2), which is lower than the SCID VCEP threshold (<25%) for PS3_Moderate, meeting this criterion (PS3_Moderate, PMID 29772310).In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM1, PM3, PP4, and PS3_Moderate (VCEP specifications version 1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA214212/MONDO:0000573/124

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

RAG2
NM_000536.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:7U:1

Conservation

PhyloP100: 7.50

Variant links:

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 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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.

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/exons	MANE	Protein	UniProt
RAG2	NM_000536.4 link	c.1247G>T	p.Trp416Leu	missense_variant	2/2	ENST00000311485.8	NP_000527.2	P55895

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAG2	ENST00000311485.8 link	c.1247G>T	p.Trp416Leu	missense_variant	2/2	1	NM_000536.4	ENSP00000308620.4		P55895

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000437

AC:

AN:

251440

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135896

show subpopulations

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:

0.000359

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727246

show subpopulations

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:

0.000406

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Histiocytic medullary reticulosis

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from tryptophan to leucine (exon 3). (N) 0252 - Variant is homozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (11 Het, 0 Hom). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in-silico tools or highly conserved with a major amino acid change. (P) 0601 - Variant affects at least one well-established (essential) functional domain or motif. It is located on the edge of the PHD domain which has been shown to be essential for protein function and represents a hotspot for previously described variants in the gene (PMID20234091, Decipher) (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. The variant has been described in four independent patients with Omenn Syndrome or SCID, twice in ClinVar and twice in the literature (PMID29772310, Gupta 2017) (P) 1001 - Strong functional evidence supporting abnormal protein function. This variant has been shown to severely impair DH-JH and VK-JK recombination activity, as well as increase protein degradation and affect cytosolic retention (PMID20234091, 29772310) (P) 1101 - Very strong and specific phenotype match. (P) 1205 - Variant is both maternally and paternally inherited. (N) -
Likely pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

Combined immunodeficiency with skin granulomas

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 20, 2024

- -

Recombinase activating gene 2 deficiency

Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Apr 01, 2024

The c.1247G>T (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Tryptophan by Leucine at amino acid 416 (p.Trp416Leu). The Popmax Filtering AF (95% confidence) in gnomAD v.4 is 0.0002998, based on 36/91078 alleles in the South Asian population. PM2_Supporting (<0.0000588), BS1 (>0.00195), and BA1 (>0.00872) are not met. No homozygotes have been observed in gnomAD (BS2 is not met). This variant is located in the PHD domain, amino acids 414-487 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1. The variant was found in at least four individuals in the literature, with diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met. All of them are homozygous, reaching 1 point for homozygous occurrence. PM3_Moderate (PMID: 17572155). Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5pts + T-B-NK+ lymphocyte subset profile 0.5pts; the total is 1 point, PP4 is met (PMID: 29772310). The recombination activity assay showed activity of this variant compared to wildtype RAG2 is 1.4% (SEM 0.2), which is lower than the SCID VCEP threshold (<25%) for PS3_Moderate, meeting this criterion (PS3_Moderate, PMID 29772310). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM1, PM3, PP4, and PS3_Moderate (VCEP specifications version 1.0). -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Oct 30, 2018

- -

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

Nov 10, 2023

This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 416 of the RAG2 protein (p.Trp416Leu). This variant is present in population databases (rs193922572, gnomAD 0.04%). This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 16960852, 17572155, 30778343). ClinVar contains an entry for this variant (Variation ID: 36717). 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: 29772310). For these reasons, this variant has been classified as Pathogenic. -

RAG2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 13, 2023

The RAG2 c.1247G>T variant is predicted to result in the amino acid substitution p.Trp416Leu. This variant has been reported in the homozygous state in individuals with Omenn syndrome (Patient 45, Sobacchi et al. 2006. PubMed ID: 16960852; Patient 33, Tirosh et al. 2018. PubMed ID: 29772310; Patient 43, Aluri et al. 2019. PubMed ID: 30778343). Functional analyses have shown that this variant impacts protein function (Couëdel et al. 2010. PubMed ID: 20234091; Notarangelo et al. 2016. PubMed ID: 26996199; Tirosh et al. 2018. PubMed ID: 29772310). This variant is reported in 0.036% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-36614472-C-A). Taken together, we interpret this variant as pathogenic. -

Inborn error of immunity;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

0.89

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

D;D

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-6.2

D;.

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.96

MutPred

0.89

Gain of disorder (P = 0.1068);Gain of disorder (P = 0.1068);

MVP

0.98

MPC

0.58

ClinPred

0.83

GERP RS

5.5

Varity_R

0.90

gMVP

0.70

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over