chr11-36593074-A-G

Position:

chr11-36593074-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP7BS1

This summary comes from the ClinGen Evidence Repository: The NM_000536.4:c.1095T>C variant is a synonymous (silent) variant (p.Ser365=) with no predicted splice impact (BP7). This variant has not been reported in the literature in individuals with RAG2-related conditions. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00314 (79/25120) in the Finnish population, which is higher than the ClinGen SCID VCEP's threshold for BS1 (>0.00195). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive SCID based on the ACMG criteria applied BS1 and BP7, as specified by the ClinGen SCID VCEP (VCEP specifications 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5950474/MONDO:0000573/124

Frequency

Genomes: 𝑓 0.0013 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 3 hom. )

Consequence

RAG2
NM_000536.4 synonymous

Scores

Clinical Significance

Likely benign reviewed by expert panel B:10

Conservation

PhyloP100: 3.04

Variant links:

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]

RAG2 links:

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 links:

RAG2 (HGNC:):

RAG2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAG2	NM_000536.4 linkuse as main transcript	c.1095T>C	p.Ser365Ser	synonymous_variant	2/2	ENST00000311485.8	NP_000527.2	P55895

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAG2	ENST00000311485.8 linkuse as main transcript	c.1095T>C	p.Ser365Ser	synonymous_variant	2/2	1	NM_000536.4	ENSP00000308620.4		P55895

Frequencies

GnomAD3 genomes

AF:

0.00131

AC:

200

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00226

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00165

AC:

414

AN:

251346

Hom.:

AF XY:

0.00160

AC XY:

217

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.000665

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000555

Gnomad FIN exome

AF:

0.00323

Gnomad NFE exome

AF:

0.00246

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00181

AC:

2644

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

1284

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.000421

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000661

Gnomad4 FIN exome

AF:

0.00352

Gnomad4 NFE exome

AF:

0.00202

Gnomad4 OTH exome

AF:

0.00159

GnomAD4 genome

AF:

0.00131

AC:

200

AN:

152288

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.00226

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00189

Hom.:

Bravo

AF:

0.00111

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00164

EpiControl

AF:

0.00178

ClinVar

Significance: Likely benign

Submissions summary: Benign:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Histiocytic medullary reticulosis

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 13, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Recombinase activating gene 2 deficiency

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Nov 14, 2023

The NM_000536.4:c.1095T>C variant is a synonymous (silent) variant (p.Ser365=) with no predicted splice impact (BP7). This variant has not been reported in the literature in individuals with RAG2-related conditions. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00314 (79/25120) in the Finnish population, which is higher than the ClinGen SCID VCEP's threshold for BS1 (>0.00195). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive SCID based on the ACMG criteria applied BS1 and BP7, as specified by the ClinGen SCID VCEP (VCEP specifications 1). -

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

7.2

DANN

Benign

0.90

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over