chr12-68809249-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_002392.6(MDM2):c.56C>T(p.Ala19Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,944 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: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
MDM2
NM_002392.6 missense
NM_002392.6 missense
Scores
4
11
Clinical Significance
Conservation
PhyloP100: 3.02
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]
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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=0.21402389).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MDM2 | NM_002392.6 | c.56C>T | p.Ala19Val | missense_variant | 2/11 | ENST00000258149.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MDM2 | ENST00000258149.11 | c.56C>T | p.Ala19Val | missense_variant | 2/11 | 1 | NM_002392.6 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152086Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461858Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727236
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152086Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74276
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 19, 2023 | The c.56C>T (p.A19V) alteration is located in exon 2 (coding exon 2) of the MDM2 gene. This alteration results from a C to T substitution at nucleotide position 56, causing the alanine (A) at amino acid position 19 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Accelerated tumor formation, susceptibility to Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 19 of the MDM2 protein (p.Ala19Val). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MDM2-related conditions. 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 disruptive. 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;.;.;.;D;D;D;.;D;D;.;.
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Uncertain
T
REVEL
Benign
Sift4G
Benign
T;T;D;T;T;T;D;D;T;D;D;D;D;D;D;T;T;D;D
Polyphen
P;.;P;P;P;.;.;.;.;.;P;P;D;P;.;P;.;.;.
Vest4
MutPred
0.35
.;Gain of catalytic residue at A13 (P = 8e-04);Gain of catalytic residue at A13 (P = 8e-04);.;Gain of catalytic residue at A13 (P = 8e-04);Gain of catalytic residue at A13 (P = 8e-04);Gain of catalytic residue at A13 (P = 8e-04);Gain of catalytic residue at A13 (P = 8e-04);Gain of catalytic residue at A13 (P = 8e-04);Gain of catalytic residue at A13 (P = 8e-04);Gain of catalytic residue at A13 (P = 8e-04);Gain of catalytic residue at A13 (P = 8e-04);Gain of catalytic residue at A13 (P = 8e-04);Gain of catalytic residue at A13 (P = 8e-04);Gain of catalytic residue at A13 (P = 8e-04);Gain of catalytic residue at A13 (P = 8e-04);Gain of catalytic residue at A13 (P = 8e-04);.;.;
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at