chr11-36593525-G-A

Variant names:

• chr11-36593525-G-A
• rs35691292
• NM_000536.4:c.644C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.644C>T (NM_000536.4) variant in RAG2 is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid 215 (p.Thr215Ile).The filtering allele frequency (the lower threshold of the 95% CI of 2177/91084 alleles) of the c.644C>T variant in RAG2 is 0.02308 for South Asian chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1, and therefore meets this criterion (BA1). Additionally, 42 homozygous individuals have been described (40 and 2 individuals in South Asian and "Remaining" populations, respectively (BS2_Supporting).In summary, this variant meets the criteria to be classified as Benign for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BA1 and BS2_Supporting (VCEP specifications version 1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA122864/MONDO:0000573/124

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (41 hom.)
• Consequence: RAG2 NM_000536.4 missense
• Clinical Significance: Benign reviewed by expert panel P:1 U:1 B:10
• Conservation: PhyloP100: 5.85
• Publications: 22 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: Benign. The variant received -9 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.644C>T	p.Thr215Ile	missense	Exon 2 of 2	NP_000527.2	P55895
	RAG2	NM_001243785.2		c.644C>T	p.Thr215Ile	missense	Exon 3 of 3	NP_001230714.1	P55895
	RAG2	NM_001243786.2		c.644C>T	p.Thr215Ile	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.644C>T	p.Thr215Ile	missense	Exon 2 of 2	ENSP00000308620.4	P55895
	RAG2	ENST00000527033.6	TSL:4	c.644C>T	p.Thr215Ile	missense	Exon 3 of 3	ENSP00000436895.2	P55895
	RAG2	ENST00000529083.2	TSL:3	c.644C>T	p.Thr215Ile	missense	Exon 2 of 2	ENSP00000436327.2	P55895

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152162 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00329 AC: 826 AN: 251378 AF XY: 0.00420

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00160 AC: 2339 AN: 1461862 Hom.: 41 Cov.: 31 AF XY: 0.00225 AC XY: 1634 AN XY: 727228

African (AFR) AF: 0.00125 AC: 42 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39700

South Asian (SAS) AF: 0.0239 AC: 2065 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1112004

Other (OTH) AF: 0.00240 AC: 145 AN: 60396

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.00142 AC XY: 106 AN XY: 74454

African (AFR) AF: 0.00123 AC: 51 AN: 41550

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5190

South Asian (SAS) AF: 0.0232 AC: 112 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000463 Hom.: 0

Bravo AF: 0.000472

ExAC AF: 0.00358 AC: 434

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Histiocytic medullary reticulosis (2)
-	-	2	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (2)
-	1	-	Inborn error of immunity;C1832322:Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2700553:Histiocytic medullary reticulosis;CN257931:Recombinase activating gene 2 deficiency (1)
-	-	1	not provided (1)
-	-	1	Recombinase activating gene 2 deficiency (1)
-	-	1	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas (1)
1	-	-	Severe combined immunodeficiency, B cell-negative (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.048	D
Polyphen		0.51	P
Vest4		0.93
MVP		0.89
MPC		0.28
ClinPred		0.074	T
GERP RS		5.7
Varity_R		0.48
gMVP		0.56
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: rs35691292; hg19: chr11-36615075;