12-121175426-G-A

Position:

• chr12-121175426-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002562.6(P2RX7):​c.920G>A​(p.Arg307Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0135 in 1,599,356 control chromosomes in the GnomAD database, including 197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.010 (12 hom., cov: 31)
  • Exomes 𝑓: 0.014 (185 hom.)
• Consequence: P2RX7 NM_002562.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.15

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 -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor [when max_spliceai, MetaRNN, MutationTaster, PrimateAI was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.0118846).
• BP6: Variant 12-121175426-G-A is Benign according to our data. Variant chr12-121175426-G-A is described in ClinVar as [Benign]. Clinvar id is 775100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0138 (19936/1447446) while in subpopulation NFE AF= 0.0163 (17875/1098784). AF 95% confidence interval is 0.0161. There are 185 homozygotes in gnomad4_exome. There are 9621 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
P2RX7	NM_002562.6	c.920G>A	p.Arg307Gln	missense_variant	9/13	ENST00000328963.10	NP_002553.3
LOC105370032	XR_001749352.3	n.327+28072C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
P2RX7	ENST00000328963.10	c.920G>A	p.Arg307Gln	missense_variant	9/13	1	NM_002562.6	ENSP00000330696	P1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1576 AN: 151794 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.00274

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.00960

GnomAD3 exomes AF: 0.00856 AC: 2152 AN: 251470 Hom.: 15 AF XY: 0.00861 AC XY: 1170 AN XY: 135916

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.00607

Gnomad ASJ exome AF: 0.00784

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.00978

GnomAD4 exome AF: 0.0138 AC: 19936 AN: 1447446 Hom.: 185 Cov.: 28 AF XY: 0.0133 AC XY: 9621 AN XY: 720982

Gnomad4 AFR exome AF: 0.00265

Gnomad4 AMR exome AF: 0.00693

Gnomad4 ASJ exome AF: 0.00910

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000710

Gnomad4 FIN exome AF: 0.0121

Gnomad4 NFE exome AF: 0.0163

Gnomad4 OTH exome AF: 0.0119

GnomAD4 genome AF: 0.0104 AC: 1576 AN: 151910 Hom.: 12 Cov.: 31 AF XY: 0.0101 AC XY: 750 AN XY: 74254

Gnomad4 AFR AF: 0.00273

Gnomad4 AMR AF: 0.0122

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.0168

Gnomad4 NFE AF: 0.0148

Gnomad4 OTH AF: 0.00950

Alfa AF: 0.0124 Hom.: 26

Bravo AF: 0.0104

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0166 AC: 64

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0148 AC: 127

ExAC AF: 0.00807 AC: 980

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0122

EpiControl AF: 0.0111

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	0.99	D;D;D;D;N
PrimateAI	Benign	0.48	T
REVEL	Uncertain	0.40
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.82
ClinPred		0.088	T
GERP RS		5.6
Varity_R		0.17
gMVP		0.91

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: rs28360457; hg19: chr12-121613229; COSMIC: COSV99947353;