rs121918575

Variant names:

• chr11-36592817-C-G
• rs121918575
• NM_000536.4:c.1352G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2_Supporting PP1_Strong PS3_Supporting PM1 PM3 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000536.4:c.1352G>C variant in RAG2 is a missense variant predicted to cause the substitution of glycine by alanine at amino acid 451 (p.Gly451Ala). The variant has been identified in at least 8 individuals. Three individuals described by Dr. Jolan were homozygous for this variant (reaching the maximum of 1 pt for homozygous occurrence). One individual with Omenn Syndrome was heterozygous for this variant and a p.R229Q variant, which is classified as pathogenic according to the SCID VCEP specifications. The trans phase was not confirmed (0.5 points, PMID 32655540). One individual with CID was heterozygous for this variant, and p.M459L, a likely pathogenic variant classified by the SCID VCEP. The trans phase was not confirmed (0.25pt, PMID 26457731). Three other individuals were heterozygous for this variant and a VUS (p.I210T, PMID 31334206; p.G32E, PMID 26457731; p.T77N, PMID 18463379, 24331380, 26457731, 29772310). 1.75 points in total, PM3 is met.These three homozygous individuals described by Dr. Jolan are from the same family: 3 affected segregations, LOD score 1.81, PP1_Strong. The filtering allele frequency (the upper threshold of the 95% CI of 9/129174 alleles) of this variant in gnomAD v.2.1.1 is 0.00003418 for European (non-Finnish) chromosomes, which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting)This variant resides within the PHD domain region, amino acids 414-487, of RAG2, defined as a critical functional domain by the ClinGen SCID VCEP (PM1). In one study (PMID 29772310), a recombination activity assay shows that the relevant activity of the p.G451A variant to wildtype RAG2 is 66.3%, which is higher than the SCID VCEP threshold (<60%) for PS3_supporting. However, in two other studies (PMID 18463379, 24331380), the relevant activity of the variant is shown to be 30% and 27.6%, respectively, which falls in the SCID VCEP threshold (>25% and <60%) for PS3_supporting (PS3_Supporting). Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5pts + SCID gene panel or exome/genome sequencing conducted 0.5pts; the total is 1 point, PP4 is met (PMID:32655540).In summary, this variant meets the criteria to be classified as Pathogenic for SCID due to recombinase activating gene 2 deficiency. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM3, PM2_Supporting, PM1, PS3_Supporting, PP4, and PP1_Strong. (VCEP specifications version 1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA122872/MONDO:0000573/124

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: RAG2 NM_000536.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11 U:1
• Conservation: PhyloP100: 7.50
• Publications: 11 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: Genomics England PanelApp, G2P, Ambry Genetics, Orphanet
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• combined immunodeficiency due to partial RAG1 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for RAG2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.1352G>C	p.Gly451Ala	missense	Exon 2 of 2	NP_000527.2	P55895
	RAG2	NM_001243785.2		c.1352G>C	p.Gly451Ala	missense	Exon 3 of 3	NP_001230714.1	P55895
	RAG2	NM_001243786.2		c.1352G>C	p.Gly451Ala	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.1352G>C	p.Gly451Ala	missense	Exon 2 of 2	ENSP00000308620.4	P55895
	RAG1	ENST00000534663.1	TSL:1	n.*86-150C>G		intron	N/A	ENSP00000434610.1	P15918-2
	RAG2	ENST00000527033.6	TSL:4	c.1352G>C	p.Gly451Ala	missense	Exon 3 of 3	ENSP00000436895.2	P55895

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152038 Hom.: 0 Cov.: 32

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251488 AF XY: 0.0000441

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: 0.0000703

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000800 AC: 117 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.0000853 AC XY: 62 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000102 AC: 113 AN: 1112012

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152038 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74266

African (AFR) AF: 0.00 AC: 0 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15260

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000793 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MVP		0.98
MPC		0.46
ClinPred		0.57	D
GERP RS		5.4
Varity_R		0.67
gMVP		0.74
Mutation Taster		=26/74	disease causing (ClinVar)

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: rs121918575; hg19: chr11-36614367;