chr9-76655456-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_015225.3(PRUNE2):​c.8323G>A​(p.Val2775Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,612,702 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

PRUNE2
NM_015225.3 missense

Scores

19

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.00700
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.023617238).
BP6
Variant 9-76655456-C-T is Benign according to our data. Variant chr9-76655456-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3784145.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRUNE2NM_015225.3 linkc.8323G>A p.Val2775Met missense_variant Exon 10 of 19 ENST00000376718.8 NP_056040.2 Q8WUY3-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRUNE2ENST00000376718.8 linkc.8323G>A p.Val2775Met missense_variant Exon 10 of 19 5 NM_015225.3 ENSP00000365908.3 Q8WUY3-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000243
AC:
6
AN:
246900
Hom.:
0
AF XY:
0.0000298
AC XY:
4
AN XY:
134086
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000584
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000332
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000268
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000240
AC:
35
AN:
1460548
Hom.:
0
Cov.:
30
AF XY:
0.0000248
AC XY:
18
AN XY:
726408
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000673
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152154
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.0000166
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000594

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Dec 11, 2024
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
9.9
DANN
Benign
0.96
DEOGEN2
Benign
0.0055
.;.;T;T;T
Eigen
Benign
-1.0
Eigen_PC
Benign
-0.89
FATHMM_MKL
Benign
0.026
N
LIST_S2
Benign
0.79
T;T;T;T;T
M_CAP
Benign
0.0053
T
MetaRNN
Benign
0.024
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.90
.;.;N;.;.
PrimateAI
Benign
0.31
T
PROVEAN
Benign
0.29
N;.;N;.;N
REVEL
Benign
0.014
Sift
Benign
0.23
T;.;T;.;T
Sift4G
Benign
0.30
T;T;T;T;T
Polyphen
0.089
.;.;B;.;.
Vest4
0.12
MutPred
0.18
.;.;Loss of glycosylation at S2779 (P = 0.2343);Loss of glycosylation at S2779 (P = 0.2343);.;
MVP
0.21
MPC
0.084
ClinPred
0.025
T
GERP RS
-0.20
Varity_R
0.029
gMVP
0.076

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs769204874; hg19: chr9-79270372; COSMIC: COSV56316397; COSMIC: COSV56316397; API