9-76704994-G-T

Position:

• chr9-76704994-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015225.3(PRUNE2):​c.7280C>A​(p.Ala2427Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRUNE2 NM_015225.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13143227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRUNE2	NM_015225.3	c.7280C>A	p.Ala2427Glu	missense_variant	8/19	ENST00000376718.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRUNE2	ENST00000376718.8	c.7280C>A	p.Ala2427Glu	missense_variant	8/19	5	NM_015225.3	P1
PCA3	ENST00000644657.1	n.174G>T		non_coding_transcript_exon_variant	1/6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2024

The c.7280C>A (p.A2427E) alteration is located in exon 8 (coding exon 8) of the PRUNE2 gene. This alteration results from a C to A substitution at nucleotide position 7280, causing the alanine (A) at amino acid position 2427 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.56
DEOGEN2	Benign	0.010	T;T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.54	T;T;T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.3	L;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.89	N;.;N
REVEL	Benign	0.12
Sift	Benign	0.12	T;.;T
Sift4G	Benign	0.21	T;T;T
Polyphen		0.0030	B;.;.
Vest4		0.30
MutPred		0.061		Gain of loop (P = 0.1081);Gain of loop (P = 0.1081);.;
MVP		0.45
MPC		0.11
ClinPred		0.076	T
GERP RS		3.9
Varity_R		0.16
gMVP		0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-79319910;