chr11-36594134-A-G

Variant names:

• chr11-36594134-A-G
• rs146584017
• NM_000536.4:c.35T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM1_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000536.4(RAG2):c.35T>C is a missense variant predicted to cause substitution of Isoleucine by Threonine at amino acid 12 (p.Ile12Thr).This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting). The highest population minor allele frequency in gnomAD v4 is 0.001750 (151/75030) in African/African American population. (PM2_Supporting, BS1 and BA1 are not met). To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2 related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_supporting (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5950633/MONDO:0000573/124

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: RAG2 NM_000536.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1 B:2
• Conservation: PhyloP100: 2.96
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM1: 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.35T>C	p.Ile12Thr	missense	Exon 2 of 2	NP_000527.2	P55895
	RAG2	NM_001243785.2		c.35T>C	p.Ile12Thr	missense	Exon 3 of 3	NP_001230714.1	P55895
	RAG2	NM_001243786.2		c.35T>C	p.Ile12Thr	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.35T>C	p.Ile12Thr	missense	Exon 2 of 2	ENSP00000308620.4	P55895
	RAG2	ENST00000527033.6	TSL:4	c.35T>C	p.Ile12Thr	missense	Exon 3 of 3	ENSP00000436895.2	P55895
	RAG2	ENST00000529083.2	TSL:3	c.35T>C	p.Ile12Thr	missense	Exon 2 of 2	ENSP00000436327.2	P55895

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000104 AC: 26 AN: 249808 AF XY: 0.0000517

Gnomad AFR exome AF: 0.00161

Gnomad AMR exome AF: 0.0000289

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: 0.0000561 AC: 82 AN: 1461482 Hom.: 0 Cov.: 31 AF XY: 0.0000454 AC XY: 33 AN XY: 727094

African (AFR) AF: 0.00209 AC: 70 AN: 33454

American (AMR) AF: 0.0000671 AC: 3 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

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

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111680

Other (OTH) AF: 0.000132 AC: 8 AN: 60390

GnomAD4 genome AF: 0.000551 AC: 84 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74504

African (AFR) AF: 0.00195 AC: 81 AN: 41576

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000238 Hom.: 0

Bravo AF: 0.000525

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000148 AC: 18

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (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	Benign	0.075
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	14
DANN	Benign	0.85
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	-0.34	N
PhyloP100		3.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.090	N
REVEL	Uncertain	0.41
Sift	Benign	0.67	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.093
MVP		0.77
MPC		0.097
ClinPred		0.0086	T
GERP RS		2.0
PromoterAI		0.010	Neutral
Varity_R		0.037
gMVP		0.34
Mutation Taster		=93/7	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: rs146584017; hg19: chr11-36615684;