12-68809243-A-G

Position:

• chr12-68809243-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002392.6(MDM2):​c.50A>G​(p.Asp17Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000205 in 1,461,870 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: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: MDM2 NM_002392.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.41

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]

ACMG classification

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=0.21857804).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MDM2	NM_002392.6	c.50A>G	p.Asp17Gly	missense_variant	2/11	ENST00000258149.11	NP_002383.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MDM2	ENST00000258149.11	c.50A>G	p.Asp17Gly	missense_variant	2/11	1	NM_002392.6	ENSP00000258149.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Accelerated tumor formation, susceptibility to Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2023

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals affected with MDM2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 17 of the MDM2 protein (p.Asp17Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	0.0075	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	.;T;T;T;D;T;.;.;.;.;T;.;.;.;.;.;T;T;.
Eigen	Benign	0.051
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;.;.;.;D;D;D;.;D;D;.;.
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.9	.;.;.;.;L;.;.;.;.;.;.;L;L;.;.;L;.;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.9	.;N;D;N;D;D;D;D;D;D;D;D;N;N;D;D;N;N;D
REVEL	Benign	0.095
Sift	Uncertain	0.024	.;D;D;D;T;T;T;T;.;D;D;T;D;T;D;D;T;D;.
Sift4G	Uncertain	0.028	D;D;D;D;D;D;D;T;D;D;D;T;D;D;D;D;D;T;D
Polyphen		0.0	B;.;P;B;B;.;.;.;.;.;P;B;P;P;.;P;.;.;.
Vest4		0.44
MutPred		0.21		.;Gain of catalytic residue at V8 (P = 0.0045);Gain of catalytic residue at V8 (P = 0.0045);.;Gain of catalytic residue at V8 (P = 0.0045);Gain of catalytic residue at V8 (P = 0.0045);Gain of catalytic residue at V8 (P = 0.0045);Gain of catalytic residue at V8 (P = 0.0045);Gain of catalytic residue at V8 (P = 0.0045);Gain of catalytic residue at V8 (P = 0.0045);Gain of catalytic residue at V8 (P = 0.0045);Gain of catalytic residue at V8 (P = 0.0045);Gain of catalytic residue at V8 (P = 0.0045);Gain of catalytic residue at V8 (P = 0.0045);Gain of catalytic residue at V8 (P = 0.0045);Gain of catalytic residue at V8 (P = 0.0045);Gain of catalytic residue at V8 (P = 0.0045);.;.;
MVP		0.63
ClinPred		0.87	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.65
gMVP		0.46

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

Other links and lift over

dbSNP: rs746284240; hg19: chr12-69203023;