chr12-68809237-C-T

Position:

chr12-68809237-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002392.6(MDM2):c.44C>T(p.Pro15Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000468 in 1,613,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00050 ( 0 hom. )

Consequence

MDM2
NM_002392.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.901

Variant links:

Genes affected

MDM2 (HGNC:6973): (MDM2 proto-oncogene) This gene encodes a nuclear-localized E3 ubiquitin ligase. The encoded protein can promote tumor formation by targeting tumor suppressor proteins, such as p53, for proteasomal degradation. This gene is itself transcriptionally-regulated by p53. Overexpression or amplification of this locus is detected in a variety of different cancers. There is a pseudogene for this gene on chromosome 2. Alternative splicing results in a multitude of transcript variants, many of which may be expressed only in tumor cells. [provided by RefSeq, Jun 2013]

MDM2 links:

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ACMG classification

Classification made for transcript

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=0.07069111).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDM2	NM_002392.6 linkuse as main transcript	c.44C>T	p.Pro15Leu	missense_variant	2/11	ENST00000258149.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDM2	ENST00000258149.11 linkuse as main transcript	c.44C>T	p.Pro15Leu	missense_variant	2/11	1	NM_002392.6		Q00987-11

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000160

AC:

AN:

249550

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135388

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000344

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000498

AC:

728

AN:

1461768

Hom.:

Cov.:

AF XY:

0.000477

AC XY:

347

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000610

Gnomad4 OTH exome

AF:

0.000795

GnomAD4 genome

AF:

0.000184

AC:

AN:

152022

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74232

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000297

Hom.:

Bravo

AF:

0.000166

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000611

AC:

ExAC

AF:

0.000124

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Accelerated tumor formation, susceptibility to

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 03, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 15 of the MDM2 protein (p.Pro15Leu). This variant is present in population databases (rs201821879, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MDM2-related conditions. ClinVar contains an entry for this variant (Variation ID: 856511). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.49

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.32

.;T;T;T;T;T;.;.;.;.;T;.;.;.;.;.;T;T;.

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.046

LIST_S2

Uncertain

0.90

D;D;D;D;D;D;D;D;.;.;.;D;D;D;.;D;D;.;.

M_CAP

Benign

0.0032

MetaRNN

Benign

0.071

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;.;.;.;N;.;.;.;.;.;.;N;N;.;.;N;.;.;.

MutationTaster

Benign

0.54

D;D;D;D;D;D;D;D;D;D;D;D;D;N;N;N;N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.8

.;N;D;N;N;N;D;D;N;D;N;N;N;D;D;D;D;N;D

REVEL

Benign

0.061

Sift

Uncertain

0.026

.;D;D;T;T;T;D;D;.;T;D;T;D;D;D;D;T;D;.

Sift4G

Benign

0.24

T;T;D;T;T;T;D;D;T;T;D;D;D;D;D;D;T;D;D

Polyphen

0.0

B;.;B;B;B;.;.;.;.;.;B;B;B;B;.;B;.;.;.

Vest4

0.15

MVP

0.45

ClinPred

0.061

GERP RS

3.8

Varity_R

0.39

gMVP

0.20

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over