rs530978

Variant names:

• chr9-76709263-G-A
• rs530978
• NM_015225.3:c.3011C>T

Variant summary

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

The NM_015225.3(PRUNE2):​c.3011C>T​(p.Thr1004Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 1,612,692 control chromosomes in the GnomAD database, including 264,258 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 0.49 (20350 hom., cov: 31)
  • Exomes 𝑓: 0.57 (243908 hom.)
• Consequence: PRUNE2 NM_015225.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.258

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=1.0055432E-5).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRUNE2	NM_015225.3	c.3011C>T	p.Thr1004Met	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.3011C>T	p.Thr1004Met	missense_variant	Exon 8 of 19	5	NM_015225.3	ENSP00000365908.3

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74880 AN: 151856 Hom.: 20352 Cov.: 31

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.634

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.529

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.697

Gnomad NFE AF: 0.593

Gnomad OTH AF: 0.574

GnomAD3 exomes AF: 0.562 AC: 139824 AN: 248656 Hom.: 41131 AF XY: 0.567 AC XY: 76553 AN XY: 135112

Gnomad AFR exome AF: 0.250

Gnomad AMR exome AF: 0.693

Gnomad ASJ exome AF: 0.697

Gnomad EAS exome AF: 0.370

Gnomad SAS exome AF: 0.535

Gnomad FIN exome AF: 0.513

Gnomad NFE exome AF: 0.599

Gnomad OTH exome AF: 0.598

GnomAD4 exome AF: 0.573 AC: 837139 AN: 1460718 Hom.: 243908 Cov.: 56 AF XY: 0.574 AC XY: 417060 AN XY: 726722

Gnomad4 AFR exome AF: 0.247

Gnomad4 AMR exome AF: 0.682

Gnomad4 ASJ exome AF: 0.695

Gnomad4 EAS exome AF: 0.379

Gnomad4 SAS exome AF: 0.539

Gnomad4 FIN exome AF: 0.515

Gnomad4 NFE exome AF: 0.588

Gnomad4 OTH exome AF: 0.567

GnomAD4 genome AF: 0.493 AC: 74893 AN: 151974 Hom.: 20350 Cov.: 31 AF XY: 0.493 AC XY: 36571 AN XY: 74240

Gnomad4 AFR AF: 0.260

Gnomad4 AMR AF: 0.633

Gnomad4 ASJ AF: 0.706

Gnomad4 EAS AF: 0.369

Gnomad4 SAS AF: 0.531

Gnomad4 FIN AF: 0.518

Gnomad4 NFE AF: 0.593

Gnomad4 OTH AF: 0.573

Alfa AF: 0.583 Hom.: 56143

Bravo AF: 0.490

ESP6500AA AF: 0.272 AC: 854

ESP6500EA AF: 0.605 AC: 4335

ExAC AF: 0.552 AC: 66480

Asia WGS AF: 0.434 AC: 1508 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	12
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0075	T;T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.59	T;T;T
MetaRNN	Benign	0.000010	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L;.;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.1	N;.;N
REVEL	Benign	0.099
Sift	Benign	0.31	T;.;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.94	P;.;.
Vest4		0.089
MPC		0.27
ClinPred		0.025	T
GERP RS		3.0
Varity_R		0.019
gMVP		0.10

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: rs530978; hg19: chr9-79324179; COSMIC: COSV65038633;