22-17209519-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001282225.2(ADA2):c.159C>A(p.Asn53Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N53N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ADA2 NM_001282225.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.11

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 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001282225.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17925295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADA2	NM_001282225.2	c.159C>A	p.Asn53Lys	missense_variant	2/10	ENST00000399837.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADA2	ENST00000399837.8	c.159C>A	p.Asn53Lys	missense_variant	2/10	1	NM_001282225.2	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 64

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.39
Dann	Benign	0.78
DEOGEN2	Uncertain	0.52	D;D;D;D;.;.;.;D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.033	N
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N;N;N;.;N;.;N;N
REVEL	Benign	0.045
Sift	Benign	0.64	T;T;T;.;T;.;T;T
Sift4G	Benign	0.50	T;T;T;.;T;.;T;.
Polyphen		0.0	B;B;B;B;.;.;.;.
Vest4		0.063
MutPred		0.69		Gain of MoRF binding (P = 0.0298);Gain of MoRF binding (P = 0.0298);Gain of MoRF binding (P = 0.0298);Gain of MoRF binding (P = 0.0298);.;.;Gain of MoRF binding (P = 0.0298);Gain of MoRF binding (P = 0.0298);
MVP		0.088
MPC		0.049
ClinPred		0.035	T
GERP RS		-5.7
Varity_R		0.27
gMVP		0.60

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: rs362129; hg19: chr22-17690409;