11-73234436-T-C

Position:

• chr11-73234436-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002564.4(P2RY2):​c.277T>C​(p.Tyr93His) variant causes a missense change. 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: 34)
• Consequence: P2RY2 NM_002564.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.22

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
P2RY2	NM_002564.4	c.277T>C	p.Tyr93His	missense_variant	3/3	ENST00000393597.7	NP_002555.4
P2RY2	NM_176071.3	c.277T>C	p.Tyr93His	missense_variant	3/3		NP_788085.3
P2RY2	NM_176072.3	c.277T>C	p.Tyr93His	missense_variant	3/3		NP_788086.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
P2RY2	ENST00000393597.7	c.277T>C	p.Tyr93His	missense_variant	3/3	1	NM_002564.4	ENSP00000377222.2
P2RY2	ENST00000311131.6	c.277T>C	p.Tyr93His	missense_variant	3/3	1		ENSP00000310305.2
P2RY2	ENST00000393596.2	c.277T>C	p.Tyr93His	missense_variant	3/3	1		ENSP00000377221.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 56

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2023

The c.277T>C (p.Y93H) alteration is located in exon 3 (coding exon 1) of the P2RY2 gene. This alteration results from a T to C substitution at nucleotide position 277, causing the tyrosine (Y) at amino acid position 93 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.83	.;.;T
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.8	L;L;L
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.91
MutPred		0.80		Loss of catalytic residue at L88 (P = 0.0597);Loss of catalytic residue at L88 (P = 0.0597);Loss of catalytic residue at L88 (P = 0.0597);
MVP		0.86
MPC		1.1
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.86
gMVP		0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-72945481;