12-68808800-T-A

Variant names:

• chr12-68808800-T-A
• rs2279744
• NM_002392.6:c.14+309T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002392.6(MDM2):​c.14+309T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MDM2 NM_002392.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.76
• Publications: 446 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).

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.14+309T>A		intron	N/A	NP_002383.2
	MDM2	NM_001145339.2		c.14+309T>A		intron	N/A	NP_001138811.1
	MDM2	NM_001367990.1		c.-291T>A		upstream_gene	N/A	NP_001354919.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM2	ENST00000258149.11	TSL:1 MANE Select	c.14+309T>A		intron	N/A	ENSP00000258149.6
	MDM2	ENST00000258148.11	TSL:1	c.14+309T>A		intron	N/A	ENSP00000258148.7
	MDM2	ENST00000393412.7	TSL:5	c.-5+309T>A		intron	N/A	ENSP00000377064.4

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 3649

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.90
DANN	Benign	0.66
PhyloP100		-1.8
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2279744; hg19: chr12-69202580;