19-10114083-C-T

Position:

• chr19-10114083-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002566.5(P2RY11):​c.470C>T​(p.Ala157Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,448,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: P2RY11 NM_002566.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31

Genes affected

P2RY11 (HGNC:8540): (purinergic receptor P2Y11) The product of this gene belongs to the family of 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 is coupled to the stimulation of the phosphoinositide and adenylyl cyclase pathways and behaves as a selective purinoceptor. Naturally occuring read-through transcripts, resulting from intergenic splicing between this gene and an immediately upstream gene (PPAN, encoding peter pan homolog), have been found. The PPAN-P2RY11 read-through mRNA is ubiquitously expressed and encodes a fusion protein that shares identity with each individual gene product. [provided by RefSeq, Jul 2008]

PPAN-P2RY11 (HGNC:33526): (PPAN-P2RY11 readthrough) This locus represents naturally occurring read-through transcription between the adjacent PPAN and P2RY11 genes. Alternative splicing results in two transcript variants, one of which encodes a fusion protein that shares sequence identity with each individual gene product. This transcript is found to be ubiquitously expressed and is up-regulated by agents inducing granulocytic differentiation. However, its functional significance in vivo remains unclear. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06640956).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
P2RY11	NM_002566.5	c.470C>T	p.Ala157Val	missense_variant	2/2	ENST00000321826.5	NP_002557.2
PPAN-P2RY11	NM_001040664.3	c.1730C>T	p.Ala577Val	missense_variant	13/13		NP_001035754.1
PPAN-P2RY11	NM_001198690.2	c.*229C>T		3_prime_UTR_variant	13/13		NP_001185619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
P2RY11	ENST00000321826.5	c.470C>T	p.Ala157Val	missense_variant	2/2	1	NM_002566.5	ENSP00000323872.4
PPAN-P2RY11	ENST00000393796.4	c.1730C>T	p.Ala577Val	missense_variant	13/13	1		ENSP00000377385.4
PPAN-P2RY11	ENST00000428358.5	c.*229C>T		3_prime_UTR_variant	13/13	2		ENSP00000411918.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000424 AC: 1 AN: 235932 Hom.: 0 AF XY: 0.00000776 AC XY: 1 AN XY: 128882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000922

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1448136 Hom.: 0 Cov.: 35 AF XY: 0.0000111 AC XY: 8 AN XY: 720980

Gnomad4 AFR exome AF: 0.0000598

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: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000829 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Nov 18, 2022

The c.1730C>T (p.A577V) alteration is located in exon 13 (coding exon 13) of the PPAN-P2RY11 gene. This alteration results from a C to T substitution at nucleotide position 1730, causing the alanine (A) at amino acid position 577 to be replaced by a valine (V). 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	Benign	0.21
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.053	.;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.066	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.62	.;N
PROVEAN	Benign	-0.25	N;N
REVEL	Benign	0.083
Sift	Benign	0.52	T;T
Sift4G	Benign	0.95	T;T
Polyphen		0.085	.;B
Vest4		0.19
MutPred		0.67		.;Gain of catalytic residue at A157 (P = 0.1188);
MVP		0.061
MPC		0.35
ClinPred		0.19	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.46

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: rs776329867; hg19: chr19-10224759; COSMIC: COSV53451331; COSMIC: COSV53451331;