19-10113754-C-T

Variant names:

• chr19-10113754-C-T
• rs146352491
• NM_002566.5:c.141C>T

Variant summary

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

The NM_001198690.2(PPAN-P2RY11):​c.1463C>T​(p.Ala488Val) 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. 11/15 in silico tools predict a benign 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. A488D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPAN-P2RY11 NM_001198690.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.11

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=0.05120617).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P2RY11	NM_002566.5	c.141C>T	p.Gly47Gly	synonymous_variant	Exon 2 of 2	ENST00000321826.5	NP_002557.2
PPAN-P2RY11	NM_001198690.2	c.1463C>T	p.Ala488Val	missense_variant	Exon 13 of 13		NP_001185619.1
PPAN-P2RY11	NM_001040664.3	c.1401C>T	p.Gly467Gly	synonymous_variant	Exon 13 of 13		NP_001035754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P2RY11	ENST00000321826.5	c.141C>T	p.Gly47Gly	synonymous_variant	Exon 2 of 2	1	NM_002566.5	ENSP00000323872.4
PPAN-P2RY11	ENST00000393796.4	c.1401C>T	p.Gly467Gly	synonymous_variant	Exon 13 of 13	1		ENSP00000377385.4
PPAN-P2RY11	ENST00000428358.5	c.1463C>T	p.Ala488Val	missense_variant	Exon 13 of 13	2		ENSP00000411918.1
P2RY11	ENST00000471843.1	n.474C>T		non_coding_transcript_exon_variant	Exon 2 of 2	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248838 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134756

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: 0.00000899

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.57
DANN	Uncertain	0.99
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.013
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.15
MutPred		0.23		Loss of disorder (P = 0.059);
MVP		0.040
ClinPred		0.077	T
GERP RS		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs146352491; hg19: chr19-10224430;