9-76655510-A-C

Position:

• chr9-76655510-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_015225.3(PRUNE2):​c.8277-8T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,609,918 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0072 (20 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (12 hom.)
• Consequence: PRUNE2 NM_015225.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001496
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0560

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]

LOC105376095 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 9-76655510-A-C is Benign according to our data. Variant chr9-76655510-A-C is described in ClinVar as [Benign]. Clinvar id is 769753.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00715 (1089/152300) while in subpopulation AFR AF= 0.0244 (1014/41546). AF 95% confidence interval is 0.0232. There are 20 homozygotes in gnomad4. There are 538 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRUNE2	NM_015225.3	c.8277-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000376718.8
LOC105376095	XR_007061586.1	n.3413A>C		non_coding_transcript_exon_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRUNE2	ENST00000376718.8	c.8277-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_015225.3	P1

Frequencies

GnomAD3 genomes AF: 0.00711 AC: 1082 AN: 152182 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00216 AC: 530 AN: 244818 Hom.: 6 AF XY: 0.00163 AC XY: 217 AN XY: 132794

Gnomad AFR exome AF: 0.0276

Gnomad AMR exome AF: 0.00299

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000134

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000451

Gnomad OTH exome AF: 0.000839

GnomAD4 exome AF: 0.000782 AC: 1140 AN: 1457618 Hom.: 12 Cov.: 29 AF XY: 0.000665 AC XY: 482 AN XY: 724876

Gnomad4 AFR exome AF: 0.0250

Gnomad4 AMR exome AF: 0.00272

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000140

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000370

Gnomad4 OTH exome AF: 0.00201

GnomAD4 genome AF: 0.00715 AC: 1089 AN: 152300 Hom.: 20 Cov.: 32 AF XY: 0.00722 AC XY: 538 AN XY: 74480

Gnomad4 AFR AF: 0.0244

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00397 Hom.: 4

Bravo AF: 0.00819

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.91
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.018
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

LitVar

Other links and lift over

dbSNP: rs142219686; hg19: chr9-79270426;