rs937282

Variant names:

• chr12-68808017-C-G
• rs937282
• NM_002392.6:c.-461C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002392.6(MDM2):​c.-461C>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 151,986 control chromosomes in the GnomAD database, including 25,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.55 (25573 hom., cov: 31)
• Consequence: MDM2 NM_002392.6 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.21
• Publications: 16 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 12-68808017-C-G is Benign according to our data. Variant chr12-68808017-C-G is described in ClinVar as Benign. ClinVar VariationId is 1164285.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.818 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002392.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM2	NM_002392.6	MANE Select	c.-461C>G		upstream_gene	N/A	NP_002383.2	Q00987-11
	MDM2	NM_001145339.2		c.-461C>G		upstream_gene	N/A	NP_001138811.1	Q00987

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM2	ENST00000258149.11	TSL:1 MANE Select	c.-461C>G		upstream_gene	N/A	ENSP00000258149.6	Q00987-11
	MDM2	ENST00000890006.1		c.-461C>G		upstream_gene	N/A	ENSP00000560065.1
	MDM2	ENST00000951805.1		c.-461C>G		upstream_gene	N/A	ENSP00000621864.1

Frequencies

GnomAD3 genomes AF: 0.550 AC: 83598 AN: 151872 Hom.: 25524 Cov.: 31

Gnomad AFR AF: 0.825

Gnomad AMI AF: 0.540

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.313

Gnomad FIN AF: 0.456

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.497

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.551 AC: 83711 AN: 151986 Hom.: 25573 Cov.: 31 AF XY: 0.540 AC XY: 40145 AN XY: 74282

African (AFR) AF: 0.825 AC: 34246 AN: 41504

American (AMR) AF: 0.370 AC: 5650 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1268 AN: 3470

East Asian (EAS) AF: 0.295 AC: 1511 AN: 5130

South Asian (SAS) AF: 0.312 AC: 1507 AN: 4826

European-Finnish (FIN) AF: 0.456 AC: 4823 AN: 10566

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.487 AC: 33041 AN: 67892

Other (OTH) AF: 0.497 AC: 1047 AN: 2108

Alfa AF: 0.537 Hom.: 2949

Bravo AF: 0.558

Asia WGS AF: 0.355 AC: 1230 AN: 3468

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Accelerated tumor formation, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.60
DANN	Benign	0.39
PhyloP100		-3.2
PromoterAI		-0.040	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs937282; hg19: chr12-69201797;