22-17209533-GC-GCC

Position:

• chr22-17209533-GC-GCC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001282225.2(ADA2):​c.144_145insG​(p.Arg49AlafsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,064 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: ADA2 NM_001282225.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -0.668

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-17209533-G-GC is Pathogenic according to our data. Variant chr22-17209533-G-GC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 586963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADA2	NM_001282225.2	c.144_145insG	p.Arg49AlafsTer13	frameshift_variant	2/10	ENST00000399837.8	NP_001269154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA2	ENST00000399837.8	c.144_145insG	p.Arg49AlafsTer13	frameshift_variant	2/10	1	NM_001282225.2	ENSP00000382731	P1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151910 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461154 Hom.: 0 Cov.: 34 AF XY: 0.0000151 AC XY: 11 AN XY: 726908

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151910 Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2 AN XY: 74186

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Oct 25, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	- -

Vasculitis due to ADA2 deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 14, 2023

This sequence change creates a premature translational stop signal (p.Arg49Alafs*13) in the ADA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADA2 are known to be pathogenic (PMID: 24552284, 24552285). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with ADA2 deficiency (PMID: 27514238). ClinVar contains an entry for this variant (Variation ID: 586963). For these reasons, this variant has been classified as Pathogenic. -

Sneddon syndrome;C3887654:Vasculitis due to ADA2 deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 18, 2022

- -

Splenomegaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Immunogenetics Laboratory, Johns Hopkins All Children's Hospital

Apr 19, 2018

The Arg49Alafs*13 variant has been reported in two cases with hemolytic anemia or CVID like presentation (Tal Ben-Ami 2016). Additionally, ADA2 protein level was extremely low in our CVID patient with this variant. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs756881285; hg19: chr22-17690423;