9-76703486-C-G

Position:

• chr9-76703486-C-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_015225.3(PRUNE2):​c.8127G>C​(p.Pro2709=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00511 in 1,613,216 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0052 (36 hom.)
• Consequence: PRUNE2 NM_015225.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.64

Genes affected

PRUNE2 (HGNC:25209): (prune homolog 2 with BCH domain) The protein encoded by this gene belongs to the B-cell CLL/lymphoma 2 and adenovirus E1B 19 kDa interacting family, whose members play roles in many cellular processes including apotosis, cell transformation, and synaptic function. Several functions for this protein have been demonstrated including suppression of Ras homolog family member A activity, which results in reduced stress fiber formation and suppression of oncogenic cellular transformation. A high molecular weight isoform of this protein has also been shown to colocalize with Adaptor protein complex 2, beta-Adaptin and endodermal markers, suggesting an involvement in post-endocytic trafficking. In prostate cancer cells, this gene acts as a tumor suppressor and its expression is regulated by prostate cancer antigen 3, a non-protein coding gene on the opposite DNA strand in an intron of this gene. Prostate cancer antigen 3 regulates levels of this gene through formation of a double-stranded RNA that undergoes adenosine deaminase actin on RNA-dependent adenosine-to-inosine RNA editing. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2015]

PCA3 (HGNC:8637): (prostate cancer associated 3) This gene produces a spliced, long non-coding RNA that is highly overexpressed in most types of prostate cancer cells and is used as a specific biomarker for this type of cancer. This gene is embedded in an intronic region of the prune2 gene on the opposite DNA strand. The transcript regulates prune2 levels through formation of a double-stranded RNA that undergoes adenosine deaminase acting on RNA-dependent adenosine-to-inosine RNA editing. In prostate cancer derived cells, overexpression of PCA induced downregulation of prune2, leading to decreased cell proliferation. Conversely, silencing in prostate cancer cells resulted in increased proliferation. Regulation of this gene appears to be sensitive to androgen-receptor activation, a molecular signature of prostate cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 9-76703486-C-G is Benign according to our data. Variant chr9-76703486-C-G is described in ClinVar as [Benign]. Clinvar id is 772912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.64 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRUNE2	NM_015225.3	c.8127G>C	p.Pro2709=	synonymous_variant	9/19	ENST00000376718.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRUNE2	ENST00000376718.8	c.8127G>C	p.Pro2709=	synonymous_variant	9/19	5	NM_015225.3	P1

Frequencies

GnomAD3 genomes AF: 0.00434 AC: 658 AN: 151662 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.000703

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00500

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00479

Gnomad FIN AF: 0.00153

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00627

Gnomad OTH AF: 0.00627

GnomAD3 exomes AF: 0.00488 AC: 1209 AN: 247674 Hom.: 9 AF XY: 0.00510 AC XY: 686 AN XY: 134614

Gnomad AFR exome AF: 0.000846

Gnomad AMR exome AF: 0.00346

Gnomad ASJ exome AF: 0.0177

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00396

Gnomad FIN exome AF: 0.00177

Gnomad NFE exome AF: 0.00627

Gnomad OTH exome AF: 0.00631

GnomAD4 exome AF: 0.00519 AC: 7586 AN: 1461436 Hom.: 36 Cov.: 55 AF XY: 0.00519 AC XY: 3776 AN XY: 726980

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00373

Gnomad4 ASJ exome AF: 0.0190

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00472

Gnomad4 FIN exome AF: 0.00191

Gnomad4 NFE exome AF: 0.00538

Gnomad4 OTH exome AF: 0.00585

GnomAD4 genome AF: 0.00433 AC: 657 AN: 151780 Hom.: 5 Cov.: 31 AF XY: 0.00414 AC XY: 307 AN XY: 74134

Gnomad4 AFR AF: 0.000701

Gnomad4 AMR AF: 0.00499

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.00479

Gnomad4 FIN AF: 0.00153

Gnomad4 NFE AF: 0.00625

Gnomad4 OTH AF: 0.00620

Alfa AF: 0.00427 Hom.: 1

Bravo AF: 0.00436

Asia WGS AF: 0.00115 AC: 4 AN: 3478

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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 25, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.033
DANN	Benign	0.67

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: rs41288765; hg19: chr9-79318402;