chr12-68818230-A-G

Variant names:

• chr12-68818230-A-G
• rs3730536
• NM_002392.6:c.308+1285A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002392.6(MDM2):​c.308+1285A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 152,108 control chromosomes in the GnomAD database, including 9,427 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 0.32 (9427 hom., cov: 32)
• Consequence: MDM2 NM_002392.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.65
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.521 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM2	NM_002392.6	MANE Select	c.308+1285A>G		intron	N/A	NP_002383.2
	MDM2	NM_001367990.1		c.290+1285A>G		intron	N/A	NP_001354919.1
	MDM2	NM_001145337.3		c.290+1285A>G		intron	N/A	NP_001138809.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM2	ENST00000258149.11	TSL:1 MANE Select	c.308+1285A>G		intron	N/A	ENSP00000258149.6
	MDM2	ENST00000539479.6	TSL:1	c.290+1285A>G		intron	N/A	ENSP00000444430.2
	MDM2	ENST00000350057.9	TSL:1	c.215+1285A>G		intron	N/A	ENSP00000266624.9

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48675 AN: 151990 Hom.: 9431 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.292

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.535

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.423

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.363

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

GnomAD4 genome AF: 0.320 AC: 48667 AN: 152108 Hom.: 9427 Cov.: 32 AF XY: 0.330 AC XY: 24538 AN XY: 74364

African (AFR) AF: 0.106 AC: 4416 AN: 41532

American (AMR) AF: 0.486 AC: 7416 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 1777 AN: 3472

East Asian (EAS) AF: 0.535 AC: 2768 AN: 5176

South Asian (SAS) AF: 0.538 AC: 2600 AN: 4832

European-Finnish (FIN) AF: 0.423 AC: 4462 AN: 10548

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.354 AC: 24087 AN: 67976

Other (OTH) AF: 0.361 AC: 758 AN: 2098

Alfa AF: 0.275 Hom.: 1136

Bravo AF: 0.315

Asia WGS AF: 0.481 AC: 1673 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.029
DANN	Benign	0.64
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3730536; hg19: chr12-69212010;