rs146584017

Positions:

chr11-36594134-A-G

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.35T>C is a missense variant predicted to cause substitution of Isoleucine by Threonine at amino acid 12 (p.Ile12Thr).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 0.001750 (151/75030) in African/African American 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/CA5950633/MONDO:0000573/124

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

RAG2
NM_000536.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:1B:2

Conservation

PhyloP100: 2.96

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

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 linkuse as main transcript	c.35T>C	p.Ile12Thr	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 linkuse as main transcript	c.35T>C	p.Ile12Thr	missense_variant	2/2	1	NM_000536.4	ENSP00000308620	P1

Frequencies

GnomAD3 genomes

AF:

0.000552

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00195

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000104

AC:

AN:

249808

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135424

show subpopulations

Gnomad AFR exome

AF:

0.00161

Gnomad AMR exome

AF:

0.0000289

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000561

AC:

AN:

1461482

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.00209

Gnomad4 AMR exome

AF:

0.0000671

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000551

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00195

Gnomad4 AMR

AF:

0.0000653

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:

0.0000920

Hom.:

Bravo

AF:

0.000525

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000148

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Recombinase activating gene 2 deficiency

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Jun 10, 2024

NM_000536.4(RAG2):c.35T>C is a missense variant predicted to cause substitution of Isoleucine by Threonine at amino acid 12 (p.Ile12Thr).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 0.001750 (151/75030) in African/African American 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). -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Aug 30, 2024

Variant summary: RAG2 c.35T>C (p.Ile12Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 249808 control chromosomes, predominantly at a frequency of 0.0016 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.61 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAG2 causing Severe Combined Immunodeficiency phenotype (0.00061). To our knowledge, no occurrence of c.35T>C in individuals affected with Severe Combined Immunodeficiency and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 573475). Based on the evidence outlined above, the variant was classified as likely benign. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.20

T;T;.;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.54

.;T;T;T

M_CAP

Benign

0.042

MetaRNN

Benign

0.015

T;T;T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

-0.34

N;N;.;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.34

PROVEAN

Benign

0.090

N;.;N;N

REVEL

Uncertain

0.41

Sift

Benign

0.67

T;.;T;T

Sift4G

Benign

0.53

T;T;.;.

Polyphen

0.0

B;B;.;.

Vest4

0.093

MVP

0.77

MPC

0.097

ClinPred

0.0086

GERP RS

2.0

Varity_R

0.037

gMVP

0.34

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