chr12-132620033-A-G

Variant names:

• chr12-132620033-A-G
• rs142844880
• NM_170682.4:c.491A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001282164.2(P2RX2):​c.386-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,590,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: P2RX2 NM_001282164.2 splice_acceptor, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.27
• Publications: 4 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.096).
• BP6: Variant 12-132620033-A-G is Benign according to our data. Variant chr12-132620033-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 501253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 140 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282164.2. 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
	P2RX2	NM_170682.4	MANE Select	c.491A>G	p.Gln164Arg	missense	Exon 5 of 11	NP_733782.1
	P2RX2	NM_170683.4		c.491A>G	p.Gln164Arg	missense	Exon 5 of 10	NP_733783.1
	P2RX2	NM_016318.4		c.419A>G	p.Gln140Arg	missense	Exon 4 of 10	NP_057402.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P2RX2	ENST00000643471.2	MANE Select	c.491A>G	p.Gln164Arg	missense	Exon 5 of 11	ENSP00000494644.1
	P2RX2	ENST00000343948.8	TSL:1	c.491A>G	p.Gln164Arg	missense	Exon 5 of 10	ENSP00000343339.4
	P2RX2	ENST00000350048.9	TSL:1	c.419A>G	p.Gln140Arg	missense	Exon 4 of 10	ENSP00000343904.5

Frequencies

GnomAD3 genomes AF: 0.000920 AC: 140 AN: 152094 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000725 AC: 153 AN: 210910 AF XY: 0.000743

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.000541

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000866

Gnomad OTH exome AF: 0.00204

GnomAD4 exome AF: 0.00106 AC: 1522 AN: 1438392 Hom.: 0 Cov.: 35 AF XY: 0.00103 AC XY: 737 AN XY: 713270

African (AFR) AF: 0.000121 AC: 4 AN: 33194

American (AMR) AF: 0.00192 AC: 79 AN: 41144

Ashkenazi Jewish (ASJ) AF: 0.000506 AC: 13 AN: 25676

East Asian (EAS) AF: 0.00 AC: 0 AN: 38712

South Asian (SAS) AF: 0.00 AC: 0 AN: 82286

European-Finnish (FIN) AF: 0.0000593 AC: 3 AN: 50584

Middle Eastern (MID) AF: 0.000192 AC: 1 AN: 5200

European-Non Finnish (NFE) AF: 0.00125 AC: 1373 AN: 1102092

Other (OTH) AF: 0.000823 AC: 49 AN: 59504

GnomAD4 genome AF: 0.000920 AC: 140 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.000981 AC XY: 73 AN XY: 74410

African (AFR) AF: 0.000289 AC: 12 AN: 41548

American (AMR) AF: 0.00405 AC: 62 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000897 AC: 61 AN: 67992

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.000889 Hom.: 0

Bravo AF: 0.00120

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000584 AC: 5

ExAC AF: 0.000382 AC: 46

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	P2RX2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	0.092
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Benign	0.077	D
PhyloP100		3.3
ClinPred		0.027	T
GERP RS		5.1
Varity_R		0.13
Mutation Taster		=50/50	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs142844880; hg19: chr12-133196619;