11-36593841-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2_SupportingPM1_Supporting

This summary comes from the ClinGen Evidence Repository: The c.328A>C (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Methionine by Leucine at amino acid 110 (p.Met110Leu). The filtering allele frequency (the upper threshold of the 95% CI of 7/1180032alleles) of the c.328A>C variant in RAG2 is 0.000001940 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).This variant is located in the core domain, amino acids 1-383 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID:26996199); PM1_Supporting.The variant has a mean recombination activity of 74.6% (SEM 1.8) compared to WT hRAG2, which is higher than 60% of wild-type activity (to be considered at least a supporting level). So, PS3 is not applied at any strength level. (PMID:29772310).At least one patient in the literature seems to be a carrier of this variant (PMID:29772310); however, the complete genetic and clinical information for the patient is not available. PP4 is not met.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting and PM1_Supporting (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA214221/MONDO:0000573/124

Frequency

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

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

RAG2
NM_000536.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:3

Conservation

PhyloP100: 3.26

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

For more information check the summary or visit ClinGen Evidence Repository.

PM2

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 link	c.328A>C	p.Met110Leu	missense_variant	Exon 2 of 2	ENST00000311485.8	NP_000527.2	P55895

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAG2	ENST00000311485.8 link	c.328A>C	p.Met110Leu	missense_variant	Exon 2 of 2	1	NM_000536.4	ENSP00000308620.4		P55895

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152232

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727236

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74368

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Severe combined immunodeficiency disease

Pathogenic:1

Aug 18, 2011

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Recombinase activating gene 2 deficiency

Uncertain:1

May 13, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.328A>C (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Methionine by Leucine at amino acid 110 (p.Met110Leu). The filtering allele frequency (the upper threshold of the 95% CI of 7/1180032 alleles) of the c.328A>C variant in RAG2 is 0.000001940 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant is located in the core domain, amino acids 1-383 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1_Supporting. The variant has a mean recombination activity of 74.6% (SEM 1.8) compared to WT hRAG2, which is higher than 60% of wild-type activity (to be considered at least a supporting level). So, PS3 is not applied at any strength level. (PMID: 29772310). At least one patient in the literature seems to be a carrier of this variant (PMID: 29772310); however, the complete genetic and clinical information for the patient is not available. PP4 is not met. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting and PM1_Supporting (VCEP specifications version 1). -

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

Uncertain:1

Aug 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine with leucine at codon 110 of the RAG2 protein (p.Met110Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with RAG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 36720). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects RAG2 function (PMID: 29772310). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn error of immunity;CN257931:Recombinase activating gene 2 deficiency

Uncertain:1

Mar 06, 2018

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.038

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.33

T;T;.

Eigen

Benign

-0.12

Eigen_PC

Benign

0.079

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.90

.;D;D

M_CAP

Benign

0.0089

MetaRNN

Benign

0.27

T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.45

N;N;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.38

N;.;N

REVEL

Benign

0.10

Sift

Benign

0.030

D;.;T

Sift4G

Benign

0.99

T;T;.

Polyphen

0.0

B;B;.

Vest4

0.30

MutPred

0.51

Loss of ubiquitination at K106 (P = 0.077);Loss of ubiquitination at K106 (P = 0.077);Loss of ubiquitination at K106 (P = 0.077);

MVP

0.82

MPC

0.29

ClinPred

0.75

GERP RS

5.5

Varity_R

0.27

gMVP

0.43

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