chr22-17207107-C-T
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1PM2PM5PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R169W) has been classified as Pathogenic.
Frequency
Consequence
NM_001282225.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADA2 | NM_001282225.2 | c.506G>A | p.Arg169Gln | missense_variant | 3/10 | ENST00000399837.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADA2 | ENST00000399837.8 | c.506G>A | p.Arg169Gln | missense_variant | 3/10 | 1 | NM_001282225.2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000394 AC: 60AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000469 AC: 118AN: 251456Hom.: 0 AF XY: 0.000493 AC XY: 67AN XY: 135902
GnomAD4 exome AF: 0.000513 AC: 750AN: 1461868Hom.: 0 Cov.: 31 AF XY: 0.000494 AC XY: 359AN XY: 727238
GnomAD4 genome AF: 0.000394 AC: 60AN: 152308Hom.: 0 Cov.: 32 AF XY: 0.000389 AC XY: 29AN XY: 74458
ClinVar
Submissions by phenotype
not provided Pathogenic:9
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 15, 2022 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | ADA2: PM1:Strong, PS1, PP1, PP2, PP4, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 16, 2021 | 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). - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 19, 2019 | PS4, PS3_moderate, PM3, PP1_moderate, PP4 - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Vasculitis due to ADA2 deficiency Pathogenic:7Other:1
Likely pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 08, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 06, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Dec 02, 2020 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 24, 2020 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | 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). Advanced 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 at Invitae 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Jun 06, 2017 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Sneddon syndrome;C3887654:Vasculitis due to ADA2 deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 29, 2022 | - - |
Autoinflammatory syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Feb 17, 2017 | - - |
Inherited Immunodeficiency Diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2019 | - - |
ADA2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 27, 2024 | 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
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at