12-132621775-G-C

Variant names:

• chr12-132621775-G-C
• rs199712315
• NM_170682.4:c.1219G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_170682.4(P2RX2):​c.1219G>C​(p.Gly407Arg) 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. 16/22 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. G407S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: P2RX2 NM_170682.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.790
• Publications: 0 publications found

Genes affected

P2RX2 (HGNC:15459): (purinergic receptor P2X 2) The product of this gene belongs to the family of purinoceptors for ATP. This receptor functions as a ligand-gated ion channel. Binding to ATP mediates synaptic transmission between neurons and from neurons to smooth muscle. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Aug 2013]

P2RX2 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 41

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000280311 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03787476).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170682.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P2RX2	NM_170682.4	MANE Select	c.1219G>C	p.Gly407Arg	missense	Exon 11 of 11	NP_733782.1
	P2RX2	NM_170683.4		c.1297G>C	p.Gly433Arg	missense	Exon 10 of 10	NP_733783.1
	P2RX2	NM_016318.4		c.1147G>C	p.Gly383Arg	missense	Exon 10 of 10	NP_057402.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P2RX2	ENST00000643471.2	MANE Select	c.1219G>C	p.Gly407Arg	missense	Exon 11 of 11	ENSP00000494644.1
	P2RX2	ENST00000343948.8	TSL:1	c.1297G>C	p.Gly433Arg	missense	Exon 10 of 10	ENSP00000343339.4
	P2RX2	ENST00000350048.9	TSL:1	c.1147G>C	p.Gly383Arg	missense	Exon 10 of 10	ENSP00000343904.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.13
DANN	Benign	0.51
DEOGEN2	Benign	0.081	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.46	N
PhyloP100		-0.79
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.022
Sift	Benign	0.36	T
Sift4G	Benign	0.80	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.10		Loss of relative solvent accessibility (P = 0.107)
MVP		0.16
MPC		0.11
ClinPred		0.22	T
GERP RS		-6.3
Varity_R		0.042
gMVP		0.27

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: rs199712315; hg19: chr12-133198361;