chr12-68828812-C-G

Variant names:

• chr12-68828812-C-G
• rs1555187172
• NM_002392.6:c.565C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002392.6(MDM2):​c.565C>G​(p.Arg189Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R189C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MDM2 NM_002392.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.37
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Li-Fraumeni syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lessel-kubisch syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25885117).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM2	NM_002392.6	c.565C>G	p.Arg189Gly	missense_variant	Exon 8 of 11	ENST00000258149.11	NP_002383.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM2	ENST00000258149.11	c.565C>G	p.Arg189Gly	missense_variant	Exon 8 of 11	1	NM_002392.6	ENSP00000258149.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	.;T;D;T;.;T
Eigen	Benign	0.052
Eigen_PC	Benign	0.023
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D;D;D;D;.;D
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.26	T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.3	.;.;M;.;.;.
PhyloP100		5.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.2	.;D;D;N;N;D
REVEL	Benign	0.17
Sift	Uncertain	0.0070	.;D;D;D;.;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D
Polyphen		0.87	P;P;P;.;.;.
Vest4		0.73
MutPred		0.26		.;.;Loss of stability (P = 0.0135);Loss of stability (P = 0.0135);.;.;
MVP		0.70
ClinPred		0.95	D
GERP RS		1.9
Varity_R		0.21
gMVP		0.54
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs1555187172; hg19: chr12-69222592;