12-121133096-G-T

Position:

• chr12-121133096-G-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP3 BP6_Very_Strong BS2

The NM_002562.6(P2RX7):​c.125+1G>T variant causes a splice donor change. The variant allele was found at a frequency of 0.00726 in 1,614,138 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0075 (55 hom.)
• Consequence: P2RX7 NM_002562.6 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 4.22

Genes affected

P2RX7 (HGNC:8537): (purinergic receptor P2X 7) The product of this gene belongs to the family of purinoceptors for ATP. This receptor functions as a ligand-gated ion channel and is responsible for ATP-dependent lysis of macrophages through the formation of membrane pores permeable to large molecules. Activation of this nuclear receptor by ATP in the cytoplasm may be a mechanism by which cellular activity can be coupled to changes in gene expression. Multiple alternatively spliced variants have been identified, most of which fit nonsense-mediated decay (NMD) criteria. [provided by RefSeq, Jul 2010]

LOC105370032 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 5: Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen [when BayesDel_addAF, MutationTaster was below the threshold]
• BP6: Variant 12-121133096-G-T is Benign according to our data. Variant chr12-121133096-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 489390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
P2RX7	NM_002562.6	c.125+1G>T		splice_donor_variant		ENST00000328963.10
LOC105370032	XR_001749352.3	n.328-6255C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
P2RX7	ENST00000328963.10	c.125+1G>T		splice_donor_variant		1	NM_002562.6	P1

Frequencies

GnomAD3 genomes AF: 0.00528 AC: 804 AN: 152232 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00595

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00861

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00553 AC: 1390 AN: 251402 Hom.: 9 AF XY: 0.00575 AC XY: 781 AN XY: 135886

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00474

Gnomad ASJ exome AF: 0.00536

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.00240

Gnomad NFE exome AF: 0.00886

Gnomad OTH exome AF: 0.00896

GnomAD4 exome AF: 0.00747 AC: 10921 AN: 1461788 Hom.: 55 Cov.: 31 AF XY: 0.00735 AC XY: 5344 AN XY: 727198

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.00496

Gnomad4 ASJ exome AF: 0.00482

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00118

Gnomad4 FIN exome AF: 0.00268

Gnomad4 NFE exome AF: 0.00885

Gnomad4 OTH exome AF: 0.00649

GnomAD4 genome AF: 0.00526 AC: 802 AN: 152350 Hom.: 6 Cov.: 33 AF XY: 0.00510 AC XY: 380 AN XY: 74504

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00595

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.00860

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00757 Hom.: 12

Bravo AF: 0.00556

TwinsUK AF: 0.0146 AC: 54

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0102 AC: 88

ExAC AF: 0.00539 AC: 654

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00911

EpiControl AF: 0.00865

ClinVar

Significance: Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	D;D;D;D;D
GERP RS		4.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs35933842; hg19: chr12-121570899;