9-76710039-C-T

Variant names:

• chr9-76710039-C-T
• rs11145017
• NM_015225.3:c.2235G>A

Variant summary

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

The NM_015225.3(PRUNE2):​c.2235G>A​(p.Met745Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,613,440 control chromosomes in the GnomAD database, including 23,925 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 0.18 (2830 hom., cov: 32)
  • Exomes 𝑓: 0.16 (21095 hom.)
• Consequence: PRUNE2 NM_015225.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.406
• Publications: 17 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=1.009305E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.467 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRUNE2	NM_015225.3	MANE Select	c.2235G>A	p.Met745Ile	missense	Exon 8 of 19	NP_056040.2
	PRUNE2	NM_001308048.2		c.2235G>A	p.Met745Ile	missense	Exon 8 of 18	NP_001294977.1
	PRUNE2	NM_001308047.2		c.2235G>A	p.Met745Ile	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.2235G>A	p.Met745Ile	missense	Exon 8 of 19	ENSP00000365908.3
	PRUNE2	ENST00000443509.6	TSL:5	c.2235G>A	p.Met745Ile	missense	Exon 8 of 18	ENSP00000393843.3
	PRUNE2	ENST00000428286.5	TSL:5	c.1158G>A	p.Met386Ile	missense	Exon 8 of 19	ENSP00000397425.1

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27132 AN: 151918 Hom.: 2824 Cov.: 32

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.483

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.160

GnomAD2 exomes AF: 0.186 AC: 46076 AN: 248090 AF XY: 0.181

Gnomad AFR exome AF: 0.198

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.131

Gnomad EAS exome AF: 0.486

Gnomad FIN exome AF: 0.288

Gnomad NFE exome AF: 0.135

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.156 AC: 227335 AN: 1461404 Hom.: 21095 Cov.: 59 AF XY: 0.156 AC XY: 113202 AN XY: 726966

African (AFR) AF: 0.198 AC: 6616 AN: 33480

American (AMR) AF: 0.155 AC: 6930 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 3464 AN: 26132

East Asian (EAS) AF: 0.493 AC: 19571 AN: 39686

South Asian (SAS) AF: 0.178 AC: 15331 AN: 86210

European-Finnish (FIN) AF: 0.278 AC: 14856 AN: 53380

Middle Eastern (MID) AF: 0.0834 AC: 481 AN: 5768

European-Non Finnish (NFE) AF: 0.135 AC: 150192 AN: 1111724

Other (OTH) AF: 0.164 AC: 9894 AN: 60360

GnomAD4 genome AF: 0.179 AC: 27153 AN: 152036 Hom.: 2830 Cov.: 32 AF XY: 0.187 AC XY: 13908 AN XY: 74298

African (AFR) AF: 0.196 AC: 8123 AN: 41478

American (AMR) AF: 0.153 AC: 2333 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 447 AN: 3470

East Asian (EAS) AF: 0.483 AC: 2491 AN: 5158

South Asian (SAS) AF: 0.187 AC: 901 AN: 4818

European-Finnish (FIN) AF: 0.284 AC: 2989 AN: 10534

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9358 AN: 67988

Other (OTH) AF: 0.161 AC: 340 AN: 2110

Alfa AF: 0.155 Hom.: 4991

Bravo AF: 0.173

TwinsUK AF: 0.133 AC: 492

ALSPAC AF: 0.128 AC: 493

ESP6500AA AF: 0.200 AC: 627

ESP6500EA AF: 0.123 AC: 882

ExAC AF: 0.184 AC: 22175

Asia WGS AF: 0.338 AC: 1177 AN: 3478

EpiCase AF: 0.123

EpiControl AF: 0.125

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.056
DANN	Benign	0.45
DEOGEN2	Benign	0.0049	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.087	T
MetaRNN	Benign	0.00010	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.41
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.060
Sift	Benign	0.45	T
Sift4G	Benign	0.49	T
Polyphen		0.0	B
Vest4		0.059
MutPred		0.058		Loss of glycosylation at P744 (P = 0.1214)
MPC		0.092
ClinPred		0.0037	T
GERP RS		-0.97
PromoterAI		-0.0056	Neutral
Varity_R		0.060
gMVP		0.13
Mutation Taster		=98/2	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: rs11145017; hg19: chr9-79324955; COSMIC: COSV65039043;