11-36593011-G-T

Variant names:

• chr11-36593011-G-T
• rs34629171
• NM_000536.4:c.1158C>A

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 NM_000536.4:c.1158C>A variant in RAG2 is a missense variant predicted to cause substitution of phenylalanine by leucine at amino acid 386 (p.Phe386Leu). This variant has a population max filtering allele frequency of 0.01649 in the European (non-Finnish) population in gnomAD, which is above the threshold for BA1 set by the ClinGen SCID VCEP for RAG2 (>0.00872). In addition, this variant is present in 23 homozygotes in gnomAD (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG criteria applied: BA1 and BS2_Supporting as specified by the ClinGen SCID VCEP (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA293061/MONDO:0000573/124

• Frequency:
  • Genomes: 𝑓 0.010 (17 hom., cov: 32)
  • Exomes 𝑓: 0.015 (190 hom.)
• Consequence: RAG2 ENST00000311485.8 missense
• Clinical Significance: Benign reviewed by expert panel B:14
• Conservation: PhyloP100: 1.58
• Publications: 14 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: Orphanet, G2P, Genomics England PanelApp, Ambry Genetics
• 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• combined immunodeficiency due to partial RAG1 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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: ENST00000311485.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAG2	NM_000536.4	MANE Select	c.1158C>A	p.Phe386Leu	missense	Exon 2 of 2	NP_000527.2
	RAG2	NM_001243785.2		c.1158C>A	p.Phe386Leu	missense	Exon 3 of 3	NP_001230714.1
	RAG2	NM_001243786.2		c.1158C>A	p.Phe386Leu	missense	Exon 3 of 3	NP_001230715.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAG2	ENST00000311485.8	TSL:1 MANE Select	c.1158C>A	p.Phe386Leu	missense	Exon 2 of 2	ENSP00000308620.4
	RAG1	ENST00000534663.1	TSL:1	n.*130G>T		non_coding_transcript_exon	Exon 10 of 10	ENSP00000434610.1
	RAG1	ENST00000534663.1	TSL:1	n.*130G>T		3_prime_UTR	Exon 10 of 10	ENSP00000434610.1

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1552 AN: 152164 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.0527

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00967 AC: 2431 AN: 251334 AF XY: 0.00951

Gnomad AFR exome AF: 0.00339

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.0167

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.0153 AC: 22401 AN: 1461846 Hom.: 190 Cov.: 31 AF XY: 0.0149 AC XY: 10820 AN XY: 727222

African (AFR) AF: 0.00242 AC: 81 AN: 33480

American (AMR) AF: 0.00264 AC: 118 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00199 AC: 52 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00123 AC: 106 AN: 86258

European-Finnish (FIN) AF: 0.0144 AC: 767 AN: 53388

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

European-Non Finnish (NFE) AF: 0.0185 AC: 20594 AN: 1111996

Other (OTH) AF: 0.0112 AC: 677 AN: 60396

GnomAD4 genome AF: 0.0102 AC: 1551 AN: 152282 Hom.: 17 Cov.: 32 AF XY: 0.00945 AC XY: 704 AN XY: 74460

African (AFR) AF: 0.00286 AC: 119 AN: 41564

American (AMR) AF: 0.00765 AC: 117 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4818

European-Finnish (FIN) AF: 0.0106 AC: 113 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0167 AC: 1135 AN: 68016

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.0139 Hom.: 67

Bravo AF: 0.0100

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0187 AC: 72

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0141 AC: 121

ExAC AF: 0.0103 AC: 1244

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0125

EpiControl AF: 0.0143

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Histiocytic medullary reticulosis (2)
-	-	1	Inborn error of immunity;CN257931:Recombinase activating gene 2 deficiency (1)
-	-	1	Recombinase activating gene 2 deficiency (1)
-	-	1	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (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, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas;C2700553:Histiocytic medullary reticulosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		1.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.020	D
Polyphen		0.99	D
Vest4		0.80
MutPred		0.56		Gain of catalytic residue at F386 (P = 0.0875)
MPC		0.47
ClinPred		0.020	T
GERP RS		4.5
Varity_R		0.74
gMVP		0.65
Mutation Taster		=77/23	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: rs34629171; hg19: chr11-36614561;