rs587777242

Positions:

• chr22-17191773-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 Uncertain_significance. Variant got 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 id is 120307.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADA2	NM_001282225.2	c.791G>C	p.Trp264Ser	missense_variant	5/10	ENST00000399837.8	NP_001269154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA2	ENST00000399837.8	c.791G>C	p.Trp264Ser	missense_variant	5/10	1	NM_001282225.2	ENSP00000382731	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Vasculitis due to ADA2 deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 06, 2014

- -

Computational scores

Source: dbNSFP v4.3

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;D;D;.;D;D;.;.
Eigen	Benign	0.095
Eigen_PC	Benign	-0.031
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.71	T;.;.;T;.;T;.;T
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.22	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-8.7	.;D;D;D;D;.;D;.
REVEL	Pathogenic	0.85
Sift	Benign	0.065	.;T;T;T;T;.;T;.
Sift4G	Benign	0.38	T;T;T;T;T;.;T;.
Polyphen		1.0, 0.78	.;D;D;P;D;D;.;.
Vest4		0.66
MutPred		0.53		.;Gain of disorder (P = 0.0028);Gain of disorder (P = 0.0028);.;Gain of disorder (P = 0.0028);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

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: rs587777242; hg19: chr22-17672663;