rs754413772

chr11-36592849-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PP5_Moderate BP4

The NM_000536.4(RAG2):c.1320A>C(p.Lys440Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RAG2 NM_000536.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.183

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000536.4
• PP5: Variant 11-36592849-T-G is Pathogenic according to our data. Variant chr11-36592849-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496626.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.01791811).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAG2	NM_000536.4	c.1320A>C	p.Lys440Asn	missense_variant	2/2	ENST00000311485.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAG2	ENST00000311485.8	c.1320A>C	p.Lys440Asn	missense_variant	2/2	1	NM_000536.4	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 3 AN: 151290 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000444

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000215 AC: 313 AN: 1457796 Hom.: 0 Cov.: 31 AF XY: 0.000201 AC XY: 146 AN XY: 724988

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.0000675

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.0000814

Gnomad4 FIN exome AF: 0.00281

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000283

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000198 AC: 3 AN: 151290 Hom.: 0 Cov.: 32 AF XY: 0.0000406 AC XY: 3 AN XY: 73848

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000444

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00500 AC: 607

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn error of immunity;C2700553:Histiocytic medullary reticulosis;CN257931:Recombinase activating gene 2 deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

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

Mar 06, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;D
Eigen	Benign	0.061
Eigen_PC	Benign	0.015
FATHMM_MKL	Uncertain	0.81	D
MetaRNN	Benign	0.018	T;T
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.1	N;.
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.61	P;P
Vest4		0.92
MutPred		0.87		Loss of methylation at K440 (P = 0.003);Loss of methylation at K440 (P = 0.003);
MVP		0.93
MPC		0.38
ClinPred		0.086	T
GERP RS		0.35
Varity_R		0.55
gMVP		0.60

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: rs754413772; hg19: chr11-36614399; COSMIC: COSV57560299; COSMIC: COSV57560299;