rs150762709

Variant names:

• chr11-36594147-C-T
• rs150762709
• NM_000536.4:c.22G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS2_Supporting BS1

This summary comes from the ClinGen Evidence Repository: The NM_000536.4:c.22G>A variant in RAG2 is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 8 (p.Val8Ile). This variant has a population max filtering allele frequency of 0.004397 in gnomAD, which is above the threshold for BS1 set by the ClinGen SCID VCEP for RAG2 (>0.00195). This variant has not been identified in individuals with SCID, though it has been identified in one individual with CID (PMID:28769923) who carried a co-occurring variant p.D200H (phase unknown, p.D200H not curated by ClinGen SCID VCEP). In addition, this variant is present in 5 homozygotes in gnomAD (BS2_Supporting). In summary, this variant is classified as a Likely Benign for autosomal recessive SCID based on the ACMG criteria applied: BS1 and BS2_Supporting as specified by the ClinGen SCID VCEP (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA293055/MONDO:0000573/124

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (21 hom.)
• Consequence: RAG2 NM_000536.4 missense
• Clinical Significance: Likely benign reviewed by expert panel B:12
• Conservation: PhyloP100: 1.29
• Publications: 12 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]

IFTAP (HGNC:25142): (intraflagellar transport associated protein) This gene encodes a protein that was identified as a cellular interacting partner of non-structural protein 10 of the severe acute respiratory syndrome coronavirus (SARS-CoV). The encoded protein may function as a negative regulator of transcription. There is a pseudogene for this gene on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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.22G>A	p.Val8Ile	missense	Exon 2 of 2	NP_000527.2	P55895
	RAG2	NM_001243785.2		c.22G>A	p.Val8Ile	missense	Exon 3 of 3	NP_001230714.1	P55895
	RAG2	NM_001243786.2		c.22G>A	p.Val8Ile	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.22G>A	p.Val8Ile	missense	Exon 2 of 2	ENSP00000308620.4	P55895
	RAG2	ENST00000527033.6	TSL:4	c.22G>A	p.Val8Ile	missense	Exon 3 of 3	ENSP00000436895.2	P55895
	RAG2	ENST00000529083.2	TSL:3	c.22G>A	p.Val8Ile	missense	Exon 2 of 2	ENSP00000436327.2	P55895

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 465 AN: 152200 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00445

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00351 AC: 873 AN: 248640 AF XY: 0.00345

Gnomad AFR exome AF: 0.000463

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.0167

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00277

Gnomad NFE exome AF: 0.00473

Gnomad OTH exome AF: 0.00413

GnomAD4 exome AF: 0.00458 AC: 6689 AN: 1459636 Hom.: 21 Cov.: 30 AF XY: 0.00448 AC XY: 3253 AN XY: 726320

African (AFR) AF: 0.000658 AC: 22 AN: 33410

American (AMR) AF: 0.00116 AC: 52 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0162 AC: 423 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00160 AC: 138 AN: 86210

European-Finnish (FIN) AF: 0.00272 AC: 145 AN: 53332

Middle Eastern (MID) AF: 0.00677 AC: 39 AN: 5764

European-Non Finnish (NFE) AF: 0.00501 AC: 5564 AN: 1110048

Other (OTH) AF: 0.00507 AC: 306 AN: 60336

GnomAD4 genome AF: 0.00306 AC: 466 AN: 152318 Hom.: 3 Cov.: 32 AF XY: 0.00266 AC XY: 198 AN XY: 74484

African (AFR) AF: 0.000601 AC: 25 AN: 41566

American (AMR) AF: 0.00242 AC: 37 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3472

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

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4828

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00445 AC: 303 AN: 68018

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00451 Hom.: 10

Bravo AF: 0.00291

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00313 AC: 380

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00387

EpiControl AF: 0.00397

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	Histiocytic medullary reticulosis (3)
-	-	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	Benign	0.085
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.057
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.0070	T
MetaSVM	Uncertain	-0.035	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.3
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.17
Sift	Benign	0.12	T
Sift4G	Benign	0.14	T
Polyphen		0.0010	B
Vest4		0.079
MVP		0.88
MPC		0.31
ClinPred		0.010	T
GERP RS		4.8
PromoterAI		-0.013	Neutral
Varity_R		0.058
gMVP		0.096
Mutation Taster		=97/3	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: rs150762709; hg19: chr11-36615697; COSMIC: COSV57558472; COSMIC: COSV57558472;