rs2227973

Variant names:

• chr11-36575763-A-G
• rs2227973
• NM_000448.3:c.2459A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-36575763-A-G
• chr11-36575763-A-C
• chr11-36575763-A-T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The NM_000448.3:c.2459A>G variant in RAG1 is a missense variant predicted to cause the substitution of Lysine by Arginine at amino acid 820 (p.Lys820Arg). The filtering allele frequency (the lower threshold of the 95% CI of 26338/44862) of the c.2459A>G variant in RAG1 is 0.5818 for East 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, 22786 homozygous adults are reported on gnomAD v.4, BS2_Supporting is Met.In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5950267/MONDO:0000572/123

• Frequency:
  • Genomes: 𝑓 0.14 (2323 hom., cov: 33)
  • Exomes 𝑓: 0.14 (20463 hom.)
• Consequence: RAG1 NM_000448.3 missense
• Clinical Significance: Benign reviewed by expert panel B:13
• Conservation: PhyloP100: 2.86
• Publications: 45 publications found

Genes affected

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]

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_000448.3. 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
	RAG1	NM_000448.3	MANE Select	c.2459A>G	p.Lys820Arg	missense	Exon 2 of 2	NP_000439.2	P15918-1
	RAG1	NM_001377277.1		c.2459A>G	p.Lys820Arg	missense	Exon 5 of 5	NP_001364206.1	P15918-1
	RAG1	NM_001377278.1		c.2459A>G	p.Lys820Arg	missense	Exon 4 of 4	NP_001364207.1	P15918-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAG1	ENST00000299440.6	TSL:1 MANE Select	c.2459A>G	p.Lys820Arg	missense	Exon 2 of 2	ENSP00000299440.5	P15918-1
	RAG1	ENST00000534663.1	TSL:1	n.2459A>G		non_coding_transcript_exon	Exon 8 of 10	ENSP00000434610.1	P15918-2
	RAG1	ENST00000697713.1		c.2459A>G	p.Lys820Arg	missense	Exon 3 of 3	ENSP00000513411.1	P15918-1

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21427 AN: 152140 Hom.: 2319 Cov.: 33

Gnomad AFR AF: 0.0997

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.579

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.0865

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.149

GnomAD2 exomes AF: 0.195 AC: 48854 AN: 250564 AF XY: 0.190

Gnomad AFR exome AF: 0.0982

Gnomad AMR exome AF: 0.345

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.590

Gnomad FIN exome AF: 0.0839

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.170

GnomAD4 exome AF: 0.136 AC: 198634 AN: 1461858 Hom.: 20463 Cov.: 36 AF XY: 0.139 AC XY: 101107 AN XY: 727234

African (AFR) AF: 0.0966 AC: 3235 AN: 33480

American (AMR) AF: 0.334 AC: 14955 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 4250 AN: 26136

East Asian (EAS) AF: 0.588 AC: 23348 AN: 39700

South Asian (SAS) AF: 0.252 AC: 21768 AN: 86254

European-Finnish (FIN) AF: 0.0879 AC: 4694 AN: 53414

Middle Eastern (MID) AF: 0.183 AC: 1056 AN: 5768

European-Non Finnish (NFE) AF: 0.104 AC: 115795 AN: 1111986

Other (OTH) AF: 0.158 AC: 9533 AN: 60396

GnomAD4 genome AF: 0.141 AC: 21442 AN: 152260 Hom.: 2323 Cov.: 33 AF XY: 0.147 AC XY: 10975 AN XY: 74464

African (AFR) AF: 0.0995 AC: 4137 AN: 41558

American (AMR) AF: 0.236 AC: 3611 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 566 AN: 3468

East Asian (EAS) AF: 0.579 AC: 2990 AN: 5162

South Asian (SAS) AF: 0.278 AC: 1343 AN: 4824

European-Finnish (FIN) AF: 0.0865 AC: 918 AN: 10616

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.107 AC: 7260 AN: 68016

Other (OTH) AF: 0.153 AC: 323 AN: 2116

Alfa AF: 0.124 Hom.: 5331

Bravo AF: 0.152

TwinsUK AF: 0.112 AC: 414

ALSPAC AF: 0.104 AC: 399

ESP6500AA AF: 0.108 AC: 474

ESP6500EA AF: 0.114 AC: 981

ExAC AF: 0.186 AC: 22633

Asia WGS AF: 0.371 AC: 1287 AN: 3478

EpiCase AF: 0.111

EpiControl AF: 0.113

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Histiocytic medullary reticulosis (2)
-	-	2	not provided (2)
-	-	2	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (2)
-	-	1	Combined immunodeficiency with skin granulomas (1)
-	-	1	Immunodeficiency 104 (1)
-	-	1	Recombinase activating gene 1 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	Benign	0.073
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.000045	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.9
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.099	T
Polyphen		0.0010	B
Vest4		0.019
MPC		0.15
ClinPred		0.034	T
GERP RS		2.6
Varity_R		0.14
gMVP		0.46
Mutation Taster		=89/11	polymorphism (auto)

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: rs2227973; hg19: chr11-36597313; COSMIC: COSV55024177;