22-17189979-C-G

Variant names:

• chr22-17189979-C-G
• rs746970158
• NM_001282225.2:c.935G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001282225.2(ADA2):​c.935G>C​(p.Arg312Pro) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADA2 NM_001282225.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.851

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA2	NM_001282225.2	c.935G>C	p.Arg312Pro	missense_variant	Exon 6 of 10	ENST00000399837.8	NP_001269154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA2	ENST00000399837.8	c.935G>C	p.Arg312Pro	missense_variant	Exon 6 of 10	1	NM_001282225.2	ENSP00000382731.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Vasculitis due to ADA2 deficiency Uncertain:1

Jun 05, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with ADA2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 312 of the ADA2 protein (p.Arg312Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;D;D;.;D;D;.;.
Eigen	Benign	-0.048
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.73	T;.;.;T;.;T;.;T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.53	D
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-4.8	.;D;D;D;D;.;D;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.016	.;D;D;D;D;.;D;.
Sift4G	Uncertain	0.047	D;T;T;D;T;.;T;.
Polyphen		1.0, 0.98	.;D;D;D;D;D;.;.
Vest4		0.68
MutPred		0.73		.;Loss of catalytic residue at R312 (P = 0.0443);Loss of catalytic residue at R312 (P = 0.0443);.;Loss of catalytic residue at R312 (P = 0.0443);Loss of catalytic residue at R312 (P = 0.0443);.;.;
MVP		0.90
MPC		0.31
ClinPred		0.99	D
GERP RS		3.1
Varity_R		0.95
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: -37

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs746970158; hg19: chr22-17670869;