9-76707758-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_015225.3(PRUNE2):c.4516T>C(p.Cys1506Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.775 in 1,613,106 control chromosomes in the GnomAD database, including 486,008 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1506Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.77 ( 45544 hom., cov: 32)

Exomes 𝑓: 0.78 ( 440464 hom. )

Consequence

PRUNE2
NM_015225.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.685

Publications

27 publications found

Variant links:

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]

PRUNE2 links:

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]

PCA3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.5039994E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.915 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRUNE2	NM_015225.3 link	c.4516T>C	p.Cys1506Arg	missense_variant	Exon 8 of 19	ENST00000376718.8	NP_056040.2	Q8WUY3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRUNE2	ENST00000376718.8 link	c.4516T>C	p.Cys1506Arg	missense_variant	Exon 8 of 19	5	NM_015225.3	ENSP00000365908.3		Q8WUY3-1

Frequencies

GnomAD3 genomes

AF:

0.771

AC:

117168

AN:

151996

Hom.:

45520

Cov.:

show subpopulations

Gnomad AFR

AF:

0.710

Gnomad AMI

AF:

0.556

Gnomad AMR

AF:

0.836

Gnomad ASJ

AF:

0.866

Gnomad EAS

AF:

0.936

Gnomad SAS

AF:

0.765

Gnomad FIN

AF:

0.821

Gnomad MID

AF:

0.854

Gnomad NFE

AF:

0.770

Gnomad OTH

AF:

0.812

GnomAD2 exomes

AF:

0.803

AC:

198249

AN:

246946

AF XY:

0.800

show subpopulations

Gnomad AFR exome

AF:

0.710

Gnomad AMR exome

AF:

0.871

Gnomad ASJ exome

AF:

0.859

Gnomad EAS exome

AF:

0.939

Gnomad FIN exome

AF:

0.818

Gnomad NFE exome

AF:

0.774

Gnomad OTH exome

AF:

0.805

GnomAD4 exome

AF:

0.775

AC:

1132517

AN:

1460992

Hom.:

440464

Cov.:

AF XY:

0.775

AC XY:

563542

AN XY:

726742

show subpopulations

African (AFR)

AF:

0.708

AC:

23706

AN:

33468

American (AMR)

AF:

0.864

AC:

38565

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.858

AC:

22404

AN:

26122

East Asian (EAS)

AF:

0.958

AC:

38009

AN:

39692

South Asian (SAS)

AF:

0.771

AC:

66440

AN:

86208

European-Finnish (FIN)

AF:

0.814

AC:

43382

AN:

53294

Middle Eastern (MID)

AF:

0.829

AC:

4784

AN:

5768

European-Non Finnish (NFE)

AF:

0.763

AC:

847692

AN:

1111426

Other (OTH)

AF:

0.787

AC:

47535

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

14363

28726

43088

57451

71814

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20454

40908

61362

81816

102270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.771

AC:

117256

AN:

152114

Hom.:

45544

Cov.:

AF XY:

0.777

AC XY:

57746

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.710

AC:

29452

AN:

41480

American (AMR)

AF:

0.835

AC:

12765

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.866

AC:

3005

AN:

3468

East Asian (EAS)

AF:

0.937

AC:

4853

AN:

5182

South Asian (SAS)

AF:

0.767

AC:

3693

AN:

4818

European-Finnish (FIN)

AF:

0.821

AC:

8685

AN:

10584

Middle Eastern (MID)

AF:

0.857

AC:

252

AN:

294

European-Non Finnish (NFE)

AF:

0.770

AC:

52330

AN:

67978

Other (OTH)

AF:

0.811

AC:

1714

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1334

2669

4003

5338

6672

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

866

1732

2598

3464

4330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.777

Hom.:

137185

Bravo

AF:

0.771

TwinsUK

AF:

0.757

AC:

2808

ALSPAC

AF:

0.761

AC:

2934

ESP6500AA

AF:

0.714

AC:

2238

ESP6500EA

AF:

0.764

AC:

5476

ExAC

AF:

0.796

AC:

95737

Asia WGS

AF:

0.845

AC:

2937

AN:

3478

EpiCase

AF:

0.779

EpiControl

AF:

0.787

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.0098

T;T;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.074

T;T;T

MetaRNN

Benign

8.5e-7

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;.

PhyloP100

0.69

PrimateAI

Benign

0.27

PROVEAN

Benign

0.21

N;.;N

REVEL

Benign

0.12

Sift

Benign

0.14

T;.;T

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

0.0

B;.;.

Vest4

0.016

MPC

0.15

ClinPred

0.0077

GERP RS

0.64

Varity_R

0.12

gMVP

0.29

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over