rs193922572

Variant names:

• chr11-36592922-C-A
• rs193922572
• NM_000536.4:c.1247G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-36592922-C-A
• chr11-36592922-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS3_Moderate PM1 PM3 PP4

This summary comes from the ClinGen Evidence Repository: The c.1247G>T (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Tryptophan by Leucine at amino acid 416 (p.Trp416Leu).The Popmax Filtering AF (95% confidence) in gnomAD v.4 is 0.0002998, based on 36/91078 alleles in the South Asian population. PM2_Supporting (<0.0000588), BS1 (>0.00195), and BA1 (>0.00872) are not met. No homozygotes have been observed in gnomAD (BS2 is not met).This variant is located in the PHD domain, amino acids 414-487 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID:26996199); PM1.The variant was found in at least four individuals in the literature, with diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met. All of them are homozygous, reaching 1 point for homozygous occurrence. PM3_Moderate (PMID:17572155). Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5pts + T-B-NK+ lymphocyte subset profile 0.5pts; the total is 1 point, PP4 is met (PMID:29772310).The recombination activity assay showed activity of this variant compared to wildtype RAG2 is 1.4% (SEM 0.2), which is lower than the SCID VCEP threshold (<25%) for PS3_Moderate, meeting this criterion (PS3_Moderate, PMID 29772310).In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM1, PM3, PP4, and PS3_Moderate (VCEP specifications version 1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA214212/MONDO:0000573/124

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: RAG2 NM_000536.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7 U:1
• Conservation: PhyloP100: 7.50
• Publications: 8 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

Our verdict: Likely_pathogenic. The variant received 7 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.
• PM3: 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.1247G>T	p.Trp416Leu	missense	Exon 2 of 2	NP_000527.2	P55895
	RAG2	NM_001243785.2		c.1247G>T	p.Trp416Leu	missense	Exon 3 of 3	NP_001230714.1	P55895
	RAG2	NM_001243786.2		c.1247G>T	p.Trp416Leu	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.1247G>T	p.Trp416Leu	missense	Exon 2 of 2	ENSP00000308620.4	P55895
	RAG1	ENST00000534663.1	TSL:1	n.*86-45C>A		intron	N/A	ENSP00000434610.1	P15918-2
	RAG2	ENST00000527033.6	TSL:4	c.1247G>T	p.Trp416Leu	missense	Exon 3 of 3	ENSP00000436895.2	P55895

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152144 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000437 AC: 11 AN: 251440 AF XY: 0.0000442

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25 AN XY: 727246

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: 0.000406 AC: 35 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00000473 Hom.: 0

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Histiocytic medullary reticulosis (2)
1	-	-	Combined immunodeficiency with skin granulomas (1)
-	1	-	Inborn error of immunity;C2700553:Histiocytic medullary reticulosis;CN257931:Recombinase activating gene 2 deficiency (1)
1	-	-	not provided (1)
1	-	-	RAG2-related disorder (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.89		Gain of disorder (P = 0.1068)
MVP		0.98
MPC		0.58
ClinPred		0.83	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.70
Mutation Taster		=8/92	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: rs193922572; hg19: chr11-36614472;