9-76707152-G-T

Variant names:

• chr9-76707152-G-T
• rs683866
• NM_015225.3:c.5122C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000376718.8(PRUNE2):​c.5122C>A​(p.His1708Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.588 in 1,613,426 control chromosomes in the GnomAD database, including 281,638 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.

• Frequency:
  • Genomes: 𝑓 0.54 (23291 hom., cov: 31)
  • Exomes 𝑓: 0.59 (258347 hom.)
• Consequence: PRUNE2 ENST00000376718.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01
• Publications: 27 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=5.676775E-6).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.639 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000376718.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRUNE2	NM_015225.3	MANE Select	c.5122C>A	p.His1708Asn	missense	Exon 8 of 19	NP_056040.2
	PRUNE2	NM_001308048.2		c.5122C>A	p.His1708Asn	missense	Exon 8 of 18	NP_001294977.1
	PRUNE2	NM_001308047.2		c.5122C>A	p.His1708Asn	missense	Exon 8 of 18	NP_001294976.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRUNE2	ENST00000376718.8	TSL:5 MANE Select	c.5122C>A	p.His1708Asn	missense	Exon 8 of 19	ENSP00000365908.3
	PRUNE2	ENST00000443509.6	TSL:5	c.5122C>A	p.His1708Asn	missense	Exon 8 of 18	ENSP00000393843.3
	PRUNE2	ENST00000428286.5	TSL:5	c.4045C>A	p.His1349Asn	missense	Exon 8 of 19	ENSP00000397425.1

Frequencies

GnomAD3 genomes AF: 0.544 AC: 82585 AN: 151792 Hom.: 23276 Cov.: 31

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.651

Gnomad ASJ AF: 0.722

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.571

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.605

Gnomad OTH AF: 0.611

GnomAD2 exomes AF: 0.590 AC: 146485 AN: 248234 AF XY: 0.594

Gnomad AFR exome AF: 0.392

Gnomad AMR exome AF: 0.702

Gnomad ASJ exome AF: 0.711

Gnomad EAS exome AF: 0.452

Gnomad FIN exome AF: 0.515

Gnomad NFE exome AF: 0.610

Gnomad OTH exome AF: 0.615

GnomAD4 exome AF: 0.592 AC: 865367 AN: 1461516 Hom.: 258347 Cov.: 52 AF XY: 0.593 AC XY: 431281 AN XY: 727038

African (AFR) AF: 0.393 AC: 13170 AN: 33478

American (AMR) AF: 0.692 AC: 30948 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.709 AC: 18522 AN: 26134

East Asian (EAS) AF: 0.462 AC: 18334 AN: 39698

South Asian (SAS) AF: 0.584 AC: 50348 AN: 86252

European-Finnish (FIN) AF: 0.517 AC: 27587 AN: 53374

Middle Eastern (MID) AF: 0.722 AC: 4165 AN: 5768

European-Non Finnish (NFE) AF: 0.599 AC: 666449 AN: 1111734

Other (OTH) AF: 0.594 AC: 35844 AN: 60360

GnomAD4 genome AF: 0.544 AC: 82643 AN: 151910 Hom.: 23291 Cov.: 31 AF XY: 0.543 AC XY: 40346 AN XY: 74254

African (AFR) AF: 0.403 AC: 16695 AN: 41418

American (AMR) AF: 0.650 AC: 9919 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.722 AC: 2503 AN: 3468

East Asian (EAS) AF: 0.453 AC: 2334 AN: 5154

South Asian (SAS) AF: 0.573 AC: 2752 AN: 4804

European-Finnish (FIN) AF: 0.520 AC: 5492 AN: 10560

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.605 AC: 41086 AN: 67936

Other (OTH) AF: 0.609 AC: 1287 AN: 2112

Alfa AF: 0.592 Hom.: 79796

Bravo AF: 0.546

TwinsUK AF: 0.595 AC: 2208

ALSPAC AF: 0.602 AC: 2319

ESP6500AA AF: 0.408 AC: 1278

ESP6500EA AF: 0.616 AC: 4415

ExAC AF: 0.583 AC: 70164

Asia WGS AF: 0.492 AC: 1708 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.7
DANN	Benign	0.46
DEOGEN2	Benign	0.0028	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0000057	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.0
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.061
Sift	Benign	0.39	T
Sift4G	Benign	0.32	T
Polyphen		0.0050	B
Vest4		0.11
MPC		0.099
ClinPred		0.0081	T
GERP RS		5.2
Varity_R		0.082
gMVP		0.040
Mutation Taster		=96/4	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: rs683866; hg19: chr9-79322068; COSMIC: COSV65039678; COSMIC: COSV65039678;