rs114028146

Variant names:

• chr9-76704864-C-A
• rs114028146
• NM_015225.3:c.7410G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-76704864-C-A
• chr9-76704864-C-G
• chr9-76704864-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_015225.3(PRUNE2):​c.7410G>T​(p.Pro2470Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,451,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P2470P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PRUNE2 NM_015225.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.537
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.027).
• BP7: Synonymous conserved (PhyloP=-0.537 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015225.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRUNE2	NM_015225.3	MANE Select	c.7410G>T	p.Pro2470Pro	synonymous	Exon 8 of 19	NP_056040.2	Q8WUY3-1
	PRUNE2	NM_001308048.2		c.7410G>T	p.Pro2470Pro	synonymous	Exon 8 of 18	NP_001294977.1
	PRUNE2	NM_001308047.2		c.7410G>T	p.Pro2470Pro	synonymous	Exon 8 of 18	NP_001294976.1	A0A088AWP5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRUNE2	ENST00000376718.8	TSL:5 MANE Select	c.7410G>T	p.Pro2470Pro	synonymous	Exon 8 of 19	ENSP00000365908.3	Q8WUY3-1
	PRUNE2	ENST00000443509.6	TSL:5	c.7410G>T	p.Pro2470Pro	synonymous	Exon 8 of 18	ENSP00000393843.3	A0A088AWP5
	PRUNE2	ENST00000428286.5	TSL:5	c.6333G>T	p.Pro2111Pro	synonymous	Exon 8 of 19	ENSP00000397425.1	E9PDC2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1451714 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 721184

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000300 AC: 1 AN: 33322

American (AMR) AF: 0.00 AC: 0 AN: 43234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25818

East Asian (EAS) AF: 0.00 AC: 0 AN: 39404

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106674

Other (OTH) AF: 0.00 AC: 0 AN: 60050

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.14
DANN	Benign	0.60
PhyloP100		-0.54

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: rs114028146; hg19: chr9-79319780;