rs143415103

Positions:

chr11-36594155-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM1_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000536.4(RAG2):c.14T>A is a missense variant predicted to cause substitution of Methionine by Lysine at amino acid 5 (p.Met5Lys). This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting).The highest population minor allele frequency in gnomAD v4 is 0.0003307 (389/1176246) in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2 related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_supporting (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5950635/MONDO:0000573/124

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

RAG2
NM_000536.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:7

Conservation

PhyloP100: 3.92

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 1 ACMG points.

PM1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAG2	NM_000536.4 linkuse as main transcript	c.14T>A	p.Met5Lys	missense_variant	2/2	ENST00000311485.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAG2	ENST00000311485.8 linkuse as main transcript	c.14T>A	p.Met5Lys	missense_variant	2/2	1	NM_000536.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000133

AC:

AN:

248390

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

134986

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000294

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000258

AC:

376

AN:

1457592

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

170

AN XY:

725420

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

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:

0.0000375

Gnomad4 NFE exome

AF:

0.000333

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000171

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000223

Hom.:

Bravo

AF:

0.000159

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000742

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Histiocytic medullary reticulosis

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 11, 2020	- -

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Recombinase activating gene 2 deficiency

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

May 01, 2024

NM_000536.4(RAG2):c.14T>A is a missense variant predicted to cause substitution of Methionine by Lysine at amino acid 5 (p.Met5Lys). This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting).The highest population minor allele frequency in gnomAD v4 is 0.0003307 (389/1176246) in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2 related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_supporting (VCEP specifications version 1). -

Severe combined immunodeficiency disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2022

This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 5 of the RAG2 protein (p.Met5Lys). This variant is present in population databases (rs143415103, gnomAD 0.03%). 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: 304560). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.25

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

T;T;.;.

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.68

.;T;T;T

M_CAP

Uncertain

0.085

MetaRNN

Benign

0.41

T;T;T;T

MetaSVM

Uncertain

0.51

MutationAssessor

Uncertain

2.0

M;M;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.10

N;.;N;N

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Uncertain

0.039

D;D;.;.

Polyphen

0.92

P;P;.;.

Vest4

0.72

MVP

0.94

MPC

0.13

ClinPred

0.25

GERP RS

5.7

Varity_R

0.93

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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