11-73234826-C-T

Variant names:

• chr11-73234826-C-T
• rs774505848
• NM_002564.4:c.667C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002564.4(P2RY2):​c.667C>T​(p.Arg223Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R223G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: P2RY2 NM_002564.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.538
• Publications: 0 publications found

Genes affected

P2RY2 (HGNC:8541): (purinergic receptor P2Y2) The product of this gene belongs to the family of P2 receptors, which is activated by extracellular nucleotides and subdivided into P2X ligand-gated ion channels and P2Y G-protein coupled receptors. This family has several receptor subtypes with different pharmacological selectivity, which overlaps in some cases, for various adenosine and uridine nucleotides. This receptor, found on many cell types, is activated by ATP and UTP and is reported to be overexpressed on some cancer cell types. It is involved in many cellular functions, such as proliferation, apoptosis and inflammation. Three transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Mar 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002564.4. 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
	P2RY2	NM_002564.4	MANE Select	c.667C>T	p.Arg223Trp	missense	Exon 3 of 3	NP_002555.4
	P2RY2	NM_176071.3		c.667C>T	p.Arg223Trp	missense	Exon 3 of 3	NP_788085.3	P41231
	P2RY2	NM_176072.3		c.667C>T	p.Arg223Trp	missense	Exon 3 of 3	NP_788086.3	P41231

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P2RY2	ENST00000393597.7	TSL:1 MANE Select	c.667C>T	p.Arg223Trp	missense	Exon 3 of 3	ENSP00000377222.2	P41231
	P2RY2	ENST00000311131.6	TSL:1	c.667C>T	p.Arg223Trp	missense	Exon 3 of 3	ENSP00000310305.2	P41231
	P2RY2	ENST00000393596.2	TSL:1	c.667C>T	p.Arg223Trp	missense	Exon 3 of 3	ENSP00000377221.2	P41231

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459122 Hom.: 0 Cov.: 56 AF XY: 0.00000138 AC XY: 1 AN XY: 725990

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111938

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.0060	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Benign	0.094
Eigen_PC	Benign	-0.081
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.54
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.72		Gain of catalytic residue at A222 (P = 0.0565)
MVP		0.91
MPC		0.43
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.74
gMVP		0.74
Mutation Taster		=79/21	polymorphism

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: rs774505848; hg19: chr11-72945871; COSMIC: COSV100232836; COSMIC: COSV100232836;