9-76636532-T-G

Variant names:

• chr9-76636532-T-G
• rs1840133001
• NM_015225.3:c.8989A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015225.3(PRUNE2):​c.8989A>C​(p.Ile2997Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000713 in 1,402,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PRUNE2 NM_015225.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70
• 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]

GCNT1 (HGNC:4203): (glucosaminyl (N-acetyl) transferase 1) This gene is a member of the beta-1,6-N-acetylglucosaminyltransferase gene family. It is essential to the formation of Gal beta 1-3(GlcNAc beta 1-6)GalNAc structures and the core 2 O-glycan branch. The gene coding this enzyme was originally mapped to 9q21, but was later localized to 9q13. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]

LOC105376095 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38439906).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRUNE2	NM_015225.3	c.8989A>C	p.Ile2997Leu	missense_variant	Exon 15 of 19	ENST00000376718.8	NP_056040.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRUNE2	ENST00000376718.8	c.8989A>C	p.Ile2997Leu	missense_variant	Exon 15 of 19	5	NM_015225.3	ENSP00000365908.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1402400 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 692696

African (AFR) AF: 0.00 AC: 0 AN: 32022

American (AMR) AF: 0.00 AC: 0 AN: 37128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25214

East Asian (EAS) AF: 0.00 AC: 0 AN: 36872

South Asian (SAS) AF: 0.00 AC: 0 AN: 79596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077958

Other (OTH) AF: 0.0000172 AC: 1 AN: 58104

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8989A>C (p.I2997L) alteration is located in exon 15 (coding exon 15) of the PRUNE2 gene. This alteration results from a A to C substitution at nucleotide position 8989, causing the isoleucine (I) at amino acid position 2997 to be replaced by a leucine (L). 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	Uncertain	0.47
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0073	.;T;T;T;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.38	T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.6	.;L;.;.;.
PhyloP100		4.7
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.9	N;N;.;N;N
REVEL	Benign	0.18
Sift	Benign	0.12	T;D;.;D;T
Sift4G	Benign	0.14	T;D;D;D;T
Polyphen		1.0	.;D;.;.;.
Vest4		0.59
MutPred		0.54		.;Gain of catalytic residue at I2997 (P = 0.0817);.;.;.;
MVP		0.68
MPC		0.19
ClinPred		0.93	D
GERP RS		4.9
Varity_R		0.48
gMVP		0.67
Mutation Taster		=62/38	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: rs1840133001; hg19: chr9-79251448;