11-36593841-T-C

Variant names:

• chr11-36593841-T-C
• rs193922575
• NM_000536.4:c.328A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000536.4(RAG2):​c.328A>G​(p.Met110Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M110L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAG2 NM_000536.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.26
• Publications: 4 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: Genomics England PanelApp, G2P, Orphanet
• 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: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37876594).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAG2	NM_000536.4	c.328A>G	p.Met110Val	missense_variant	Exon 2 of 2	ENST00000311485.8	NP_000527.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAG2	ENST00000311485.8	c.328A>G	p.Met110Val	missense_variant	Exon 2 of 2	1	NM_000536.4	ENSP00000308620.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251412 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Histiocytic medullary reticulosis Uncertain:1

Apr 13, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D;D;.
Eigen	Benign	0.046
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.7	L;L;.
PhyloP100		3.3
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.8	N;.;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D;.;D
Sift4G	Benign	0.11	T;T;.
Polyphen		0.0070	B;B;.
Vest4		0.55
MutPred		0.62		Loss of ubiquitination at K106 (P = 0.077);Loss of ubiquitination at K106 (P = 0.077);Loss of ubiquitination at K106 (P = 0.077);
MVP		0.85
MPC		0.30
ClinPred		0.63	D
GERP RS		5.5
Varity_R		0.61
gMVP		0.48
Mutation Taster		=85/15	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: rs193922575; hg19: chr11-36615391;