rs587777242

Variant names:

• chr22-17191773-C-G
• rs587777242
• NM_001282225.2:c.791G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001282225.2(ADA2):​c.791G>C​(p.Trp264Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ADA2 NM_001282225.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.05
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• deficiency of adenosine deaminase 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• vasculitis due to ADA2 deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• Sneddon syndrome

  Inheritance: AD, AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• polyarteritis nodosa

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• Diamond-Blackfan anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868
• PP5: Variant 22-17191773-C-G is Pathogenic according to our data. Variant chr22-17191773-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 120307.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282225.2. 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
	ADA2	NM_001282225.2	MANE Select	c.791G>C	p.Trp264Ser	missense	Exon 5 of 10	NP_001269154.1	Q9NZK5-1
	ADA2	NM_001282226.2		c.791G>C	p.Trp264Ser	missense	Exon 5 of 10	NP_001269155.1	Q9NZK5-1
	ADA2	NM_001282227.2		c.665G>C	p.Trp222Ser	missense	Exon 5 of 10	NP_001269156.1	B4E3Q4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA2	ENST00000399837.8	TSL:1 MANE Select	c.791G>C	p.Trp264Ser	missense	Exon 5 of 10	ENSP00000382731.2	Q9NZK5-1
	ADA2	ENST00000262607.3	TSL:1	c.791G>C	p.Trp264Ser	missense	Exon 4 of 9	ENSP00000262607.2	Q9NZK5-1
	ADA2	ENST00000885359.1		c.908G>C	p.Trp303Ser	missense	Exon 6 of 11	ENSP00000555418.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461416 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727078

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111738

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Vasculitis due to ADA2 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	23
DANN	Benign	0.85
DEOGEN2	Benign	0.086	T
Eigen	Benign	0.095
Eigen_PC	Benign	-0.031
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.22	D
PhyloP100		6.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-8.7	D
REVEL	Pathogenic	0.85
Sift	Benign	0.065	T
Sift4G	Benign	0.38	T
Polyphen		1.0	D
Vest4		0.66
MutPred		0.53		Gain of disorder (P = 0.0028)
MVP		0.86
MPC		0.15
ClinPred		0.96	D
GERP RS		3.6
Varity_R		0.93
gMVP		0.82
Mutation Taster		=5/95	disease causing (ClinVar)

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: rs587777242; hg19: chr22-17672663;