rs145614809

Variant names:

• chr11-36592665-T-C
• rs145614809
• NM_000536.4:c.1504A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 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. 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:8 B:5
• Conservation: PhyloP100: 1.40
• Publications: 10 publications found

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]

RAG1 Gene-Disease associations (from GenCC):

• immunodeficiency disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• Omenn syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Ambry Genetics, Orphanet
• recombinase activating gene 1 deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• combined immunodeficiency due to partial RAG1 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 0.19672 (below the threshold of 3.09). Trascript score misZ: 0.57458 (below the threshold of 3.09). GenCC associations: The gene is linked to severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, Omenn syndrome, recombinase activating gene 2 deficiency.
• 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 VariationId is 440231.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000536.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAG2	NM_000536.4	MANE Select	c.1504A>G	p.Met502Val	missense	Exon 2 of 2	NP_000527.2	P55895
	RAG2	NM_001243785.2		c.1504A>G	p.Met502Val	missense	Exon 3 of 3	NP_001230714.1	P55895
	RAG2	NM_001243786.2		c.1504A>G	p.Met502Val	missense	Exon 3 of 3	NP_001230715.1	P55895

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAG2	ENST00000311485.8	TSL:1 MANE Select	c.1504A>G	p.Met502Val	missense	Exon 2 of 2	ENSP00000308620.4	P55895
	RAG1	ENST00000534663.1	TSL:1	n.*86-302T>C		intron	N/A	ENSP00000434610.1	P15918-2
	RAG2	ENST00000527033.6	TSL:4	c.1504A>G	p.Met502Val	missense	Exon 3 of 3	ENSP00000436895.2	P55895

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

GnomAD2 exomes AF: 0.00191 AC: 480 AN: 251354 AF XY: 0.00192

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 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

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.000604 AC: 27 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00131 AC: 113 AN: 86258

European-Finnish (FIN) AF: 0.00777 AC: 415 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00196 AC: 2184 AN: 1112006

Other (OTH) AF: 0.00212 AC: 128 AN: 60396

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

African (AFR) AF: 0.000313 AC: 13 AN: 41546

American (AMR) AF: 0.000196 AC: 3 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.00717 AC: 76 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00184 AC: 125 AN: 68016

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Histiocytic medullary reticulosis (2)
-	1	1	not provided (2)
-	2	-	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (2)
-	2	-	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas;C2700553:Histiocytic medullary reticulosis (2)
-	1	-	Combined immunodeficiency with skin granulomas (1)
-	-	1	Inborn error of immunity;C2700553:Histiocytic medullary reticulosis;CN257931:Recombinase activating gene 2 deficiency (1)
-	-	1	not specified (1)
-	-	1	RAG2-related disorder (1)
-	-	1	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0088	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.4
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.45	N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.026	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
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs145614809; hg19: chr11-36614215;