12-68824258-T-G

Position:

• chr12-68824258-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002392.6(MDM2):​c.359-105T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 698,556 control chromosomes in the GnomAD database, including 69,608 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 0.43 (14786 hom., cov: 32)
  • Exomes 𝑓: 0.44 (54822 hom.)
• Consequence: MDM2 NM_002392.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.370

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MDM2	NM_002392.6	c.359-105T>G		intron_variant		ENST00000258149.11	NP_002383.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MDM2	ENST00000258149.11	c.359-105T>G		intron_variant		1	NM_002392.6	ENSP00000258149

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65938 AN: 151872 Hom.: 14774 Cov.: 32

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.532

Gnomad ASJ AF: 0.529

Gnomad EAS AF: 0.664

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.452

GnomAD4 exome AF: 0.437 AC: 238584 AN: 546566 Hom.: 54822 Cov.: 7 AF XY: 0.445 AC XY: 127219 AN XY: 285920

Gnomad4 AFR exome AF: 0.411

Gnomad4 AMR exome AF: 0.572

Gnomad4 ASJ exome AF: 0.526

Gnomad4 EAS exome AF: 0.670

Gnomad4 SAS exome AF: 0.609

Gnomad4 FIN exome AF: 0.468

Gnomad4 NFE exome AF: 0.378

Gnomad4 OTH exome AF: 0.444

GnomAD4 genome AF: 0.434 AC: 65982 AN: 151990 Hom.: 14786 Cov.: 32 AF XY: 0.444 AC XY: 32983 AN XY: 74298

Gnomad4 AFR AF: 0.419

Gnomad4 AMR AF: 0.532

Gnomad4 ASJ AF: 0.529

Gnomad4 EAS AF: 0.664

Gnomad4 SAS AF: 0.610

Gnomad4 FIN AF: 0.473

Gnomad4 NFE AF: 0.380

Gnomad4 OTH AF: 0.451

Alfa AF: 0.398 Hom.: 3439

Bravo AF: 0.438

Asia WGS AF: 0.600 AC: 2085 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	17
DANN	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2291857; hg19: chr12-69218038; COSMIC: COSV99254363; COSMIC: COSV99254363;