12-132618807-C-T

Variant names:

• chr12-132618807-C-T
• rs566193497
• NM_170682.4:c.-10C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_170682.4(P2RX2):​c.-10C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000329 in 1,237,130 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 29)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: P2RX2 NM_170682.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.19
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 12-132618807-C-T is Benign according to our data. Variant chr12-132618807-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 514570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000147 (160/1086464) while in subpopulation AMR AF = 0.0178 (136/7634). AF 95% confidence interval is 0.0154. There are 2 homozygotes in GnomAdExome4. There are 75 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 247 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P2RX2	NM_170682.4	MANE Select	c.-10C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_733782.1	Q9UBL9-1
	P2RX2	NM_170682.4	MANE Select	c.-10C>T		5_prime_UTR	Exon 1 of 11	NP_733782.1	Q9UBL9-1
	P2RX2	NM_170683.4		c.-10C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_733783.1	Q9UBL9-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P2RX2	ENST00000643471.2	MANE Select	c.-10C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000494644.1	Q9UBL9-1
	P2RX2	ENST00000643471.2	MANE Select	c.-10C>T		5_prime_UTR	Exon 1 of 11	ENSP00000494644.1	Q9UBL9-1
	P2RX2	ENST00000343948.8	TSL:1	c.-10C>T		upstream_gene	N/A	ENSP00000343339.4	Q9UBL9-4

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 244 AN: 150558 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.0000970

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.000962

GnomAD2 exomes AF: 0.000411 AC: 5 AN: 12152 AF XY: 0.000329

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0543

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000147 AC: 160 AN: 1086464 Hom.: 2 Cov.: 30 AF XY: 0.000145 AC XY: 75 AN XY: 518108

African (AFR) AF: 0.00 AC: 0 AN: 22242

American (AMR) AF: 0.0178 AC: 136 AN: 7634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12904

East Asian (EAS) AF: 0.00 AC: 0 AN: 24678

South Asian (SAS) AF: 0.00 AC: 0 AN: 24164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3330

European-Non Finnish (NFE) AF: 0.00000546 AC: 5 AN: 916336

Other (OTH) AF: 0.000451 AC: 19 AN: 42146

GnomAD4 genome AF: 0.00164 AC: 247 AN: 150666 Hom.: 1 Cov.: 29 AF XY: 0.00189 AC XY: 139 AN XY: 73572

African (AFR) AF: 0.0000967 AC: 4 AN: 41346

American (AMR) AF: 0.0157 AC: 239 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5072

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67476

Other (OTH) AF: 0.000952 AC: 2 AN: 2100

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.00297

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.4
DANN	Uncertain	0.98
PhyloP100		-2.2
PromoterAI		-0.052	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs566193497; hg19: chr12-133195393;