chr12-68808546-C-T

Variant names:

• chr12-68808546-C-T
• rs2870820
• NM_002392.6:c.14+55C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002392.6(MDM2):​c.14+55C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 1,610,530 control chromosomes in the GnomAD database, including 115,369 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8077 hom., cov: 33)
  • Exomes 𝑓: 0.38 (107292 hom.)
• Consequence: MDM2 NM_002392.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.393
• Publications: 28 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 12-68808546-C-T is Benign according to our data. Variant chr12-68808546-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 695297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.404 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM2	NM_002392.6	MANE Select	c.14+55C>T		intron	N/A	NP_002383.2	Q00987-11
	MDM2	NM_001145339.2		c.14+55C>T		intron	N/A	NP_001138811.1	Q00987

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM2	ENST00000258149.11	TSL:1 MANE Select	c.14+55C>T		intron	N/A	ENSP00000258149.6	Q00987-11
	MDM2	ENST00000258148.11	TSL:1	c.14+55C>T		intron	N/A	ENSP00000258148.7	G3XA89
	MDM2	ENST00000890006.1		c.14+55C>T		intron	N/A	ENSP00000560065.1

Frequencies

GnomAD3 genomes AF: 0.296 AC: 45060 AN: 152078 Hom.: 8077 Cov.: 33

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.522

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.294

GnomAD4 exome AF: 0.375 AC: 547128 AN: 1458334 Hom.: 107292 AF XY: 0.372 AC XY: 269501 AN XY: 725202

African (AFR) AF: 0.101 AC: 3374 AN: 33332

American (AMR) AF: 0.198 AC: 8805 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 7550 AN: 26102

East Asian (EAS) AF: 0.284 AC: 11213 AN: 39496

South Asian (SAS) AF: 0.239 AC: 20557 AN: 86086

European-Finnish (FIN) AF: 0.419 AC: 22316 AN: 53230

Middle Eastern (MID) AF: 0.240 AC: 1342 AN: 5582

European-Non Finnish (NFE) AF: 0.407 AC: 451268 AN: 1109796

Other (OTH) AF: 0.344 AC: 20703 AN: 60158

GnomAD4 genome AF: 0.296 AC: 45065 AN: 152196 Hom.: 8077 Cov.: 33 AF XY: 0.294 AC XY: 21846 AN XY: 74394

African (AFR) AF: 0.112 AC: 4675 AN: 41556

American (AMR) AF: 0.222 AC: 3400 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1009 AN: 3472

East Asian (EAS) AF: 0.281 AC: 1455 AN: 5170

South Asian (SAS) AF: 0.241 AC: 1164 AN: 4824

European-Finnish (FIN) AF: 0.421 AC: 4458 AN: 10586

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.408 AC: 27728 AN: 67982

Other (OTH) AF: 0.296 AC: 625 AN: 2114

Alfa AF: 0.342 Hom.: 1701

Bravo AF: 0.274

Asia WGS AF: 0.269 AC: 933 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Accelerated tumor formation, susceptibility to (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.9
DANN	Benign	0.69
PhyloP100		0.39
PromoterAI		0.041	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2870820; hg19: chr12-69202326; COSMIC: COSV50699381; COSMIC: COSV50699381;