9-76709825-T-C

Position:

• chr9-76709825-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015225.3(PRUNE2):​c.2449A>G​(p.Asn817Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 1,613,244 control chromosomes in the GnomAD database, including 267,173 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.52 (21642 hom., cov: 31)
  • Exomes 𝑓: 0.58 (245531 hom.)
• Consequence: PRUNE2 NM_015225.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.28

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.0732673E-6).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRUNE2	NM_015225.3	c.2449A>G	p.Asn817Asp	missense_variant	8/19	ENST00000376718.8	NP_056040.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRUNE2	ENST00000376718.8	c.2449A>G	p.Asn817Asp	missense_variant	8/19	5	NM_015225.3	ENSP00000365908	P1
PCA3	ENST00000644657.1	n.736+4269T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79013 AN: 151760 Hom.: 21634 Cov.: 31

Gnomad AFR AF: 0.356

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.644

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.367

Gnomad SAS AF: 0.532

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.593

Gnomad OTH AF: 0.591

GnomAD3 exomes AF: 0.570 AC: 141338 AN: 248070 Hom.: 41588 AF XY: 0.573 AC XY: 77180 AN XY: 134804

Gnomad AFR exome AF: 0.346

Gnomad AMR exome AF: 0.697

Gnomad ASJ exome AF: 0.697

Gnomad EAS exome AF: 0.370

Gnomad SAS exome AF: 0.540

Gnomad FIN exome AF: 0.513

Gnomad NFE exome AF: 0.599

Gnomad OTH exome AF: 0.603

GnomAD4 exome AF: 0.576 AC: 842119 AN: 1461366 Hom.: 245531 Cov.: 61 AF XY: 0.577 AC XY: 419307 AN XY: 726946

Gnomad4 AFR exome AF: 0.349

Gnomad4 AMR exome AF: 0.687

Gnomad4 ASJ exome AF: 0.695

Gnomad4 EAS exome AF: 0.379

Gnomad4 SAS exome AF: 0.543

Gnomad4 FIN exome AF: 0.515

Gnomad4 NFE exome AF: 0.588

Gnomad4 OTH exome AF: 0.575

GnomAD4 genome AF: 0.521 AC: 79057 AN: 151878 Hom.: 21642 Cov.: 31 AF XY: 0.520 AC XY: 38592 AN XY: 74244

Gnomad4 AFR AF: 0.356

Gnomad4 AMR AF: 0.643

Gnomad4 ASJ AF: 0.706

Gnomad4 EAS AF: 0.367

Gnomad4 SAS AF: 0.535

Gnomad4 FIN AF: 0.518

Gnomad4 NFE AF: 0.593

Gnomad4 OTH AF: 0.589

Alfa AF: 0.583 Hom.: 47200

Bravo AF: 0.522

TwinsUK AF: 0.584 AC: 2165

ALSPAC AF: 0.590 AC: 2273

ESP6500AA AF: 0.369 AC: 1156

ESP6500EA AF: 0.605 AC: 4333

ExAC AF: 0.561 AC: 67507

Asia WGS AF: 0.449 AC: 1559 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T;T;T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.039
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.55	T;T;T
MetaRNN	Benign	0.0000061	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	0.80	P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.4	N;.;N
REVEL	Benign	0.073
Sift	Benign	0.041	D;.;D
Sift4G	Benign	0.16	T;T;T
Polyphen		0.38	B;.;.
Vest4		0.37
MPC		0.12
ClinPred		0.013	T
GERP RS		5.7
Varity_R		0.16
gMVP		0.28

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: rs557352; hg19: chr9-79324741; COSMIC: COSV65038637;