chr12-68808048-C-G

Variant names:

• chr12-68808048-C-G
• rs3730491
• NM_002392.6:c.-430C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002392.6(MDM2):​c.-430C>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000741 in 430,236 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00089 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (0 hom.)
• Consequence: MDM2 NM_002392.6 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.15

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM2	NM_002392.6	c.-430C>G		upstream_gene_variant		ENST00000258149.11	NP_002383.2
MDM2	NM_001145339.2	c.-430C>G		upstream_gene_variant			NP_001138811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM2	ENST00000258149.11	c.-430C>G		upstream_gene_variant		1	NM_002392.6	ENSP00000258149.6
MDM2	ENST00000393412.7	c.-448C>G		upstream_gene_variant		5		ENSP00000377064.4
MDM2	ENST00000311420.13	n.-430C>G		upstream_gene_variant		5		ENSP00000310742.9
MDM2	ENST00000493419.1	n.-234C>G		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.000894 AC: 136 AN: 152110 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.000658 AC: 183 AN: 278008 Hom.: 0 AF XY: 0.000685 AC XY: 98 AN XY: 143166

Gnomad4 AFR exome AF: 0.000705

Gnomad4 AMR exome AF: 0.00407

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000132

Gnomad4 SAS exome AF: 0.0000844

Gnomad4 FIN exome AF: 0.0000421

Gnomad4 NFE exome AF: 0.000647

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.000893 AC: 136 AN: 152228 Hom.: 1 Cov.: 32 AF XY: 0.000941 AC XY: 70 AN XY: 74426

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.0000530 Hom.: 0

Bravo AF: 0.00140

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.75
DANN	Benign	0.42

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3730491; hg19: chr12-69201828;