chr11-36593607-C-T

Variant names:

• chr11-36593607-C-T
• rs1554947160
• NM_000536.4:c.562G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_000536.4(RAG2):​c.562G>A​(p.Glu188Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E188Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAG2 NM_000536.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.77
• Publications: 0 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]

RAG2 Gene-Disease associations (from GenCC):

• Omenn syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• recombinase activating gene 2 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000536.4
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.808

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.562G>A	p.Glu188Lys	missense	Exon 2 of 2	NP_000527.2	P55895
	RAG2	NM_001243785.2		c.562G>A	p.Glu188Lys	missense	Exon 3 of 3	NP_001230714.1	P55895
	RAG2	NM_001243786.2		c.562G>A	p.Glu188Lys	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.562G>A	p.Glu188Lys	missense	Exon 2 of 2	ENSP00000308620.4	P55895
	RAG2	ENST00000527033.6	TSL:4	c.562G>A	p.Glu188Lys	missense	Exon 3 of 3	ENSP00000436895.2	P55895
	RAG2	ENST00000529083.2	TSL:3	c.562G>A	p.Glu188Lys	missense	Exon 2 of 2	ENSP00000436327.2	P55895

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.032	D
Polyphen		0.99	D
Vest4		0.61
MutPred		0.66		Gain of methylation at E188 (P = 8e-04)
MVP		0.98
MPC		0.47
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.60
gMVP		0.78
Mutation Taster		=75/25	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: rs1554947160; hg19: chr11-36615157; COSMIC: COSV57556295; COSMIC: COSV57556295;