rs145614809

chr11-36592665-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000536.4(RAG2):c.1504A>G(p.Met502Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,614,138 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (5 hom.)
• Consequence: RAG2 NM_000536.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:5
• Conservation: PhyloP100: 1.40

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008794427).
• BP6: Variant 11-36592665-T-C is Benign according to our data. Variant chr11-36592665-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 440231.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=3, Benign=2}.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAG2	NM_000536.4	c.1504A>G	p.Met502Val	missense_variant	2/2	ENST00000311485.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAG2	ENST00000311485.8	c.1504A>G	p.Met502Val	missense_variant	2/2	1	NM_000536.4	P1

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 225 AN: 152132 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00717

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.00191 AC: 480 AN: 251354 Hom.: 3 AF XY: 0.00192 AC XY: 261 AN XY: 135890

Gnomad AFR exome AF: 0.000433

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000849

Gnomad FIN exome AF: 0.00665

Gnomad NFE exome AF: 0.00228

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00197 AC: 2884 AN: 1461888 Hom.: 5 Cov.: 31 AF XY: 0.00198 AC XY: 1441 AN XY: 727244

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00131

Gnomad4 FIN exome AF: 0.00777

Gnomad4 NFE exome AF: 0.00196

Gnomad4 OTH exome AF: 0.00212

GnomAD4 genome AF: 0.00148 AC: 225 AN: 152250 Hom.: 1 Cov.: 32 AF XY: 0.00150 AC XY: 112 AN XY: 74450

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00717

Gnomad4 NFE AF: 0.00184

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.00156 Hom.: 0

Bravo AF: 0.000960

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00217 AC: 263

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

Histiocytic medullary reticulosis Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	This variant is associated with the following publications: (PMID: 17572155, 19178939, 26457731, 29772310, 16960852) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 15, 2020	- -

Combined immunodeficiency with skin granulomas Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Sep 12, 2017

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 07, 2022

Variant summary: RAG2 c.1504A>G (p.Met502Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 251354 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in RAG2 causing Severe Combined Immunodeficiency Syndrome/Omenn Syndrome phenotype (0.00071), strongly suggesting that the variant is benign. c.1504A>G has been reported in the literature in individuals affected with Severe Combined Immunodeficiency Syndrome/Omenn Syndrome (e.g. Sobacchi_2006, Sheehan_2009, Walter_2015). In at least two of these individuals, co-occurrence of the variant in cis with a RAG1 pathogenic variant was reported (RAG1 c.1303A>G, p.Met435Val; Sheehan_2009, Walter_2015), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function demonstrated the variant to have wild-type levels of recombination activity (Tirosh_2019). Three ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and five ClinVar submitters (evaluation after 2014) cite it as uncertain significance. 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

Invitae

Jan 30, 2024

- -

RAG2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn error of immunity;C2700553:Histiocytic medullary reticulosis;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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Pathogenic	0.16
Cadd	Benign	16
Dann	Benign	0.95
DEOGEN2	Uncertain	0.43	T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0088	T;T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.45	N;.
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.026	B;B
Vest4		0.20
MVP		0.92
MPC		0.078
ClinPred		0.034	T
GERP RS		0.56
Varity_R		0.57
gMVP		0.36

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: rs145614809; hg19: chr11-36614215;