9-76709825-T-C

Variant names:

• chr9-76709825-T-C
• rs557352
• NM_015225.3:c.2449A>G

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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
• Publications: 29 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PRUNE2	NM_015225.3	c.2449A>G	p.Asn817Asp	missense_variant	Exon 8 of 19	ENST00000376718.8	NP_056040.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRUNE2	ENST00000376718.8	c.2449A>G	p.Asn817Asp	missense_variant	Exon 8 of 19	5	NM_015225.3	ENSP00000365908.3

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

GnomAD2 exomes AF: 0.570 AC: 141338 AN: 248070 AF XY: 0.573

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 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

African (AFR) AF: 0.349 AC: 11691 AN: 33476

American (AMR) AF: 0.687 AC: 30696 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.695 AC: 18168 AN: 26132

East Asian (EAS) AF: 0.379 AC: 15033 AN: 39690

South Asian (SAS) AF: 0.543 AC: 46867 AN: 86246

European-Finnish (FIN) AF: 0.515 AC: 27514 AN: 53376

Middle Eastern (MID) AF: 0.712 AC: 4108 AN: 5766

European-Non Finnish (NFE) AF: 0.588 AC: 653350 AN: 1111636

Other (OTH) AF: 0.575 AC: 34692 AN: 60360

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

African (AFR) AF: 0.356 AC: 14739 AN: 41404

American (AMR) AF: 0.643 AC: 9820 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 2447 AN: 3468

East Asian (EAS) AF: 0.367 AC: 1887 AN: 5138

South Asian (SAS) AF: 0.535 AC: 2576 AN: 4814

European-Finnish (FIN) AF: 0.518 AC: 5461 AN: 10542

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.593 AC: 40316 AN: 67930

Other (OTH) AF: 0.589 AC: 1241 AN: 2108

Alfa AF: 0.571 Hom.: 62092

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;.;.
PhyloP100		1.3
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
PromoterAI		-0.0062	Neutral
Varity_R		0.16
gMVP		0.28
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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