rs769412

chr12-68839435-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_002392.6(MDM2):c.1080A>G(p.Glu360=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0622 in 1,613,782 control chromosomes in the GnomAD database, including 3,502 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.074 (510 hom., cov: 31)
  • Exomes 𝑓: 0.061 (2992 hom.)
• Consequence: MDM2 NM_002392.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.282

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 12-68839435-A-G is Benign according to our data. Variant chr12-68839435-A-G is described in ClinVar as [Benign]. Clinvar id is 1167676.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.282 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDM2	NM_002392.6	c.1080A>G	p.Glu360=	synonymous_variant	11/11	ENST00000258149.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDM2	ENST00000258149.11	c.1080A>G	p.Glu360=	synonymous_variant	11/11	1	NM_002392.6

Frequencies

GnomAD3 genomes AF: 0.0739 AC: 11222 AN: 151810 Hom.: 513 Cov.: 31

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0676

Gnomad ASJ AF: 0.0375

Gnomad EAS AF: 0.0143

Gnomad SAS AF: 0.0551

Gnomad FIN AF: 0.0233

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0599

Gnomad OTH AF: 0.0755

GnomAD3 exomes AF: 0.0548 AC: 13680 AN: 249520 Hom.: 464 AF XY: 0.0544 AC XY: 7362 AN XY: 135376

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.0407

Gnomad ASJ exome AF: 0.0410

Gnomad EAS exome AF: 0.0161

Gnomad SAS exome AF: 0.0566

Gnomad FIN exome AF: 0.0287

Gnomad NFE exome AF: 0.0608

Gnomad OTH exome AF: 0.0589

GnomAD4 exome AF: 0.0610 AC: 89135 AN: 1461854 Hom.: 2992 Cov.: 31 AF XY: 0.0607 AC XY: 44176 AN XY: 727226

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.0433

Gnomad4 ASJ exome AF: 0.0421

Gnomad4 EAS exome AF: 0.0170

Gnomad4 SAS exome AF: 0.0589

Gnomad4 FIN exome AF: 0.0312

Gnomad4 NFE exome AF: 0.0631

Gnomad4 OTH exome AF: 0.0627

GnomAD4 genome AF: 0.0739 AC: 11230 AN: 151928 Hom.: 510 Cov.: 31 AF XY: 0.0719 AC XY: 5336 AN XY: 74220

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.0674

Gnomad4 ASJ AF: 0.0375

Gnomad4 EAS AF: 0.0142

Gnomad4 SAS AF: 0.0551

Gnomad4 FIN AF: 0.0233

Gnomad4 NFE AF: 0.0599

Gnomad4 OTH AF: 0.0752

Alfa AF: 0.0658 Hom.: 306

Bravo AF: 0.0797

Asia WGS AF: 0.0420 AC: 146 AN: 3478

EpiCase AF: 0.0637

EpiControl AF: 0.0666

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Accelerated tumor formation, susceptibility to Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	6.9
Dann	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs769412; hg19: chr12-69233215; COSMIC: COSV50699998; COSMIC: COSV50699998;