rs2046112033

Variant names:

• chr9-76704061-T-C
• rs2046112033
• NM_015225.3:c.7552A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-76704061-T-C
• chr9-76704061-T-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015225.3(PRUNE2):​c.7552A>G​(p.Thr2518Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,448,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: PRUNE2 NM_015225.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.231
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.021798968).

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.7552A>G	p.Thr2518Ala	missense	Exon 9 of 19	NP_056040.2	Q8WUY3-1
	PRUNE2	NM_001308048.2		c.7552A>G	p.Thr2518Ala	missense	Exon 9 of 18	NP_001294977.1
	PRUNE2	NM_001308047.2		c.7552A>G	p.Thr2518Ala	missense	Exon 9 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.7552A>G	p.Thr2518Ala	missense	Exon 9 of 19	ENSP00000365908.3	Q8WUY3-1
	PRUNE2	ENST00000443509.6	TSL:5	c.7552A>G	p.Thr2518Ala	missense	Exon 9 of 18	ENSP00000393843.3	A0A088AWP5
	PRUNE2	ENST00000428286.5	TSL:5	c.6475A>G	p.Thr2159Ala	missense	Exon 9 of 19	ENSP00000397425.1	E9PDC2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1448912 Hom.: 0 Cov.: 35 AF XY: 0.00000416 AC XY: 3 AN XY: 720322

African (AFR) AF: 0.00 AC: 0 AN: 32782

American (AMR) AF: 0.00 AC: 0 AN: 41066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25474

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 83950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1107720

Other (OTH) AF: 0.00 AC: 0 AN: 59818

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.76
DANN	Benign	0.16
DEOGEN2	Benign	0.0058	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0082	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.23
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.020
Sift	Benign	0.097	T
Sift4G	Benign	0.47	T
Polyphen		0.0010	B
Vest4		0.033
MutPred		0.061		Loss of phosphorylation at T2518 (P = 0.0255)
MVP		0.048
MPC		0.082
ClinPred		0.051	T
GERP RS		-4.0
Varity_R		0.035
gMVP		0.056
Mutation Taster		=100/0	polymorphism

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: rs2046112033; hg19: chr9-79318977;