rs34629171

chr11-36593011-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000536.4(RAG2):c.1158C>A(p.Phe386Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 1,614,128 control chromosomes in the GnomAD database, including 207 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. F386F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (17 hom., cov: 32)
  • Exomes 𝑓: 0.015 (190 hom.)
• Consequence: RAG2 NM_000536.4 missense
• Clinical Significance: Benign reviewed by expert panel B:13
• Conservation: PhyloP100: 1.58

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]

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011342108).
• BP6: Variant 11-36593011-G-T is Benign according to our data. Variant chr11-36593011-G-T is described in ClinVar as [Benign]. Clinvar id is 138887.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr11-36593011-G-T is described in Lovd as [Likely_benign]. Variant chr11-36593011-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0102 (1551/152282) while in subpopulation NFE AF= 0.0167 (1135/68016). AF 95% confidence interval is 0.0159. There are 17 homozygotes in gnomad4. There are 704 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAG2	NM_000536.4	c.1158C>A	p.Phe386Leu	missense_variant	2/2	ENST00000311485.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAG2	ENST00000311485.8	c.1158C>A	p.Phe386Leu	missense_variant	2/2	1	NM_000536.4	P1

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1552 AN: 152164 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.0527

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00967 AC: 2431 AN: 251334 Hom.: 21 AF XY: 0.00951 AC XY: 1292 AN XY: 135836

Gnomad AFR exome AF: 0.00339

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.0167

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.0153 AC: 22401 AN: 1461846 Hom.: 190 Cov.: 31 AF XY: 0.0149 AC XY: 10820 AN XY: 727222

Gnomad4 AFR exome AF: 0.00242

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00123

Gnomad4 FIN exome AF: 0.0144

Gnomad4 NFE exome AF: 0.0185

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.0102 AC: 1551 AN: 152282 Hom.: 17 Cov.: 32 AF XY: 0.00945 AC XY: 704 AN XY: 74460

Gnomad4 AFR AF: 0.00286

Gnomad4 AMR AF: 0.00765

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0106

Gnomad4 NFE AF: 0.0167

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.0140 Hom.: 29

Bravo AF: 0.0100

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0187 AC: 72

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0141 AC: 121

ExAC AF: 0.0103 AC: 1244

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0125

EpiControl AF: 0.0143

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 10, 2019	Variant summary: RAG2 c.1158C>A (p.Phe386Leu) results in a non-conservative amino acid change in 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 0.0097 in 251334 control chromosomes, predominantly at a frequency of 0.017 within the Non-Finnish European subpopulation in the gnomAD database, including 21 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 24 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAG2 causing Severe Combined Immunodeficiency Syndrome phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. At least one publication reports experimental evidence evaluating an impact on protein function. This report suggests that the variant showed similar levels of recombination activity compared to that of wild-type (Tirosh_2019). Three ClinVar submitters (evaluation after 2014) cite the variant as benign (2x) and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	RAG2: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 25, 2022	- -

Histiocytic medullary reticulosis Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 12, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Recombinase activating gene 2 deficiency Benign:1

Benign, reviewed by expert panel

curation

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Nov 14, 2023

The NM_000536.4:c.1158C>A variant in RAG2 is a missense variant predicted to cause substitution of phenylalanine by leucine at amino acid 386 (p.Phe386Leu). This variant has a population max filtering allele frequency of 0.01649 in the European (non-Finnish) population in gnomAD, which is above the threshold for BA1 set by the ClinGen SCID VCEP for RAG2 (>0.00872). In addition, this variant is present in 23 homozygotes in gnomAD (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG criteria applied: BA1 and BS2_Supporting 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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn error of immunity;CN257931:Recombinase activating gene 2 deficiency Benign:1

Benign, criteria provided, single submitter

research

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

Mar 06, 2018

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Oct 24, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.92	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.020	D;D
Polyphen		0.99	D;D
Vest4		0.80
MutPred		0.56		Gain of catalytic residue at F386 (P = 0.0875);Gain of catalytic residue at F386 (P = 0.0875);
MPC		0.47
ClinPred		0.020	T
GERP RS		4.5
Varity_R		0.74
gMVP		0.65

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: rs34629171; hg19: chr11-36614561;