NM_001282225.2:c.506G>A

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_001282225.2(ADA2):c.506G>A(p.Arg169Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000502 in 1,614,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 0 hom. )

Consequence

ADA2
NM_001282225.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23O:1

Conservation

PhyloP100: 3.88

Variant links:

Genes affected

ADA2 (HGNC:1839): (adenosine deaminase 2) This gene encodes a member of a subfamily of the adenosine deaminase protein family. The encoded protein is one of two adenosine deaminases found in humans, which regulate levels of the signaling molecule, adenosine. The encoded protein is secreted from monocytes undergoing differentiation and may regulate cell proliferation and differentiation. This gene may be responsible for some of the phenotypic features associated with cat eye syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ADA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 22-17207107-C-T is Pathogenic according to our data. Variant chr22-17207107-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 120303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17207107-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.26673746). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA2	NM_001282225.2 link	c.506G>A	p.Arg169Gln	missense_variant	Exon 3 of 10	ENST00000399837.8	NP_001269154.1	Q9NZK5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA2	ENST00000399837.8 link	c.506G>A	p.Arg169Gln	missense_variant	Exon 3 of 10	1	NM_001282225.2	ENSP00000382731.2		Q9NZK5-1

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000558

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000469

AC:

118

AN:

251456

Hom.:

AF XY:

0.000493

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00189

Gnomad NFE exome

AF:

0.000607

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000513

AC:

750

AN:

1461868

Hom.:

Cov.:

AF XY:

0.000494

AC XY:

359

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00187

Gnomad4 NFE exome

AF:

0.000568

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000394

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.000559

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000504

Hom.:

Bravo

AF:

0.000310

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000486

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000356

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:10

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ADA2 c.506G>A; p.Arg169Gln variant (rs77563738; ClinVar Variation ID: 120303) is reported in the literature as homozygous or compound heterozygous in at least twelve probands affected with ADA2-associated disorders and also segregated with at least 9 affected relatives (Elkan 2014, Schepp 2016, Van Eyck 2014, Van Eyck 2015, Van Montfrans 2014, Van Montfrans 2016, Westendorp 2015, Zhou 2014). This variant is found in the general population with an overall allele frequency of 0.05% (134/282,860 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.87). Additionally, functional analyses demonstrate that this variant reduces secretion and activity of the protein encoded by ADA2 (Elkan 2014). Based on the available information, the p.Arg169Gln variant is considered pathogenic. References: Elkan et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med. 2014 Mar 6;370(10):921-31. PMID: 24552285. Schepp et al. Deficiency of Adenosine Deaminase 2 Causes Antibody Deficiency. J Clin Immunol. 2016 Apr;36(3):179-86. PMID: 26922074. Van Eyck et al. Hematopoietic stem cell transplantation rescues the immunologic phenotype and prevents vasculopathy in patients with adenosine deaminase 2 deficiency. J Allergy Clin Immunol. 2015 Jan;135(1):283-7.e5. PMID: 25457153. Van Eyck et al. Mutant ADA2 in vasculopathies. N Engl J Med. 2014 Jul 31;371(5):478-9. PMID: 25075848. Van Montfrans et al. Mutant ADA2 in vasculopathies. N Engl J Med. 2014 Jul 31;371(5):478. PMID: 25075845. Van Montfrans et al. Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations. Rheumatology (Oxford). 2016 May;55(5):902-10. PMID: 26867732. Westendorp et al. Unexplained early-onset lacunar stroke and inflammatory skin lesions: Consider ADA2 deficiency. Neurology. 2015 May 19;84(20):2092-3. PMID: 25888558. Zhou et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. 2014 Mar 6;370(10):911-20. PMID: 24552284. -

Apr 24, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PP3, PM3_strong, PS3_moderate, PS4_moderate -

Jun 16, 2021

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the ADA2 gene demonstrated a sequence change, c.506G>A, in exon 3 that results in an amino acid change, p.Arg169Gln. This sequence change is a well-described pathogenic variant in both the homozygous and compound heterozygous state in individuals with ADA2-related disorders (PMID: 24552285, 28993957, 25457153, 29391253, 32499645, 26922074, 28493328, 30924144, 32353633). This sequence change has been described in the gnomAD database with frequency of 0.19% in the Finnish subpopulation (dbSNP rs77563738). The p.Arg169Gln change affects highly conserved amino acid residue located in a domain of the ADA2 protein that is known to be functional. Although, in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg169Gln substitution, experimental studies have demonstrated that this variant impacts ADA2 activity (PMID: 26867732, 24552285). -

Apr 15, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect; R169Q results in decreased ADA2 secretion and activity (Navon et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28830446, 27130863, 29271561, 25457153, 25075846, 25075845, 27663683, 25083540, 25888558, 24552285, 28993957, 24737293, 29736678, 25278816, 28974505, 29681619, 29391253, 29564582, 27059682, 28516235, 28493328, 28805790, 29273180, 29411230, 26867732, 26922074, 27514238, 28522451, 24552284, 30924144, 31393689, 33021335, 30386947, 31980526, 32353633, 33726816, 32499645, 32581362, 33757531, 33517505) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ADA2: PM1:Strong, PS1, PP1, PP2, PP4, PS3:Supporting -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Vasculitis due to ADA2 deficiency

Pathogenic:8Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 06, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 08, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 169 of the ADA2 protein (p.Arg169Gln). This variant is present in population databases (rs77563738, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with ADA2-related conditions (PMID: 24552284, 24552285, 25888558, 26867732). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 120303). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ADA2 protein function. Experimental studies have shown that this missense change affects ADA2 function (PMID: 24552285, 26867732). For these reasons, this variant has been classified as Pathogenic. -

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 06, 2017

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 24, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 24, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CECR1 c.506G>A (p.Arg169Gln) results in a conservative amino acid change in the encoded protein sequence. CECR1 is also known as ADA2 in the literature and databases. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 251456 control chromosomes (gnomAD). c.506G>A has been reported (in both homozygous and compound heterozygous states) in the literature in individuals affected with Polyarteritis Nodosa, Childhoood-Onset (e.g. Elkan_2014, Zhou_2014) and ADA2-deficiency (e.g. VanMontfrans_2016). In many families, the variant was reported to segregate with disease. These data indicate that the variant is very likely to be associated with disease. In functional studies performed in both patient-derived cells and in cells transfected with the variant, c.506G>A resulted in reduced enzymatic activity as well as reduced protein secretion (e.g. VanMontfrans_2016, Elkan_2014). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 02, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This ADA2 variant has been identified in numerous patients with ADA2-deficiency in both the compound heterozygous and homozygous state. ADA2 c.506G>A is located within the putative receptor-binding domain and functional studies have demonstrated that this variant causes severely decreased levels of secreted ADA2. This variant has been seen in trans with a second disease-causing ADA2 variant in affected individuals within a family. ADA2 c.506G>A (rs77563738) is present in a large population dataset (gnomAD: 134/282860 total alleles; 0.05%; no homozygotes) and has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is highly evolutionarily conserved across most species assessed. We consider this variant to be pathogenic. -

Sneddon syndrome;C3887654:Vasculitis due to ADA2 deficiency

Pathogenic:1

Apr 29, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autoinflammatory syndrome

Pathogenic:1

Feb 17, 2017

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inherited Immunodeficiency Diseases

Pathogenic:1

Jan 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

ADA2-related disorder

Pathogenic:1

Sep 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ADA2 c.506G>A variant is predicted to result in the amino acid substitution p.Arg169Gln. This variant in the compound heterozygous or homozygous state has been reported in patients with a complex immunologic and vascular phenotype, including polyarteritis nodosa (Navon Elkan et al. 2014. PubMed ID: 24552285; Van Eyck et al. 2015. PubMed ID: 25457153; Van Montfrans et al. 2016. PubMed ID: 26867732). This variant is reported in 0.19% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Sneddon syndrome

Pathogenic:1

Jan 03, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000120303, PMID:24552285, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87, 3CNET: 0.971, PP3_P). A missense variant is a common mechanism associated with Sneddon syndrome (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000474, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.14

T;T;T;T;T;.;.

Eigen

Benign

0.19

Eigen_PC

Benign

-0.074

FATHMM_MKL

Benign

0.59

LIST_S2

Uncertain

0.89

D;.;.;.;D;.;D

M_CAP

Pathogenic

0.76

MetaRNN

Benign

0.27

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.57

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-3.7

.;D;D;D;.;D;.

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

.;D;D;D;.;D;.

Sift4G

Pathogenic

0.0

D;D;D;D;.;D;.

Polyphen

1.0

.;D;D;D;D;.;.

Vest4

0.75

MVP

0.93

MPC

0.33

ClinPred

0.12

GERP RS

2.2

Varity_R

0.86

gMVP

0.76

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