rs117039649

Variant names:

• chr12-68808776-G-C
• rs117039649
• NM_002392.6:c.14+285G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002392.6(MDM2):​c.14+285G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0225 in 152,170 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.022 (63 hom., cov: 32)
• Consequence: MDM2 NM_002392.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.30
• Publications: 50 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 12-68808776-G-C is Benign according to our data. Variant chr12-68808776-G-C is described in ClinVar as Benign. ClinVar VariationId is 1168231.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0225 (3423/152170) while in subpopulation NFE AF = 0.0362 (2464/67986). AF 95% confidence interval is 0.035. There are 63 homozygotes in GnomAd4. There are 1581 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3423 AD,Unknown gene.

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+285G>C		intron	N/A	NP_002383.2	Q00987-11
	MDM2	NM_001145339.2		c.14+285G>C		intron	N/A	NP_001138811.1	Q00987
	MDM2	NM_001367990.1		c.-315G>C		upstream_gene	N/A	NP_001354919.1	Q00987-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM2	ENST00000258149.11	TSL:1 MANE Select	c.14+285G>C		intron	N/A	ENSP00000258149.6	Q00987-11
	MDM2	ENST00000258148.11	TSL:1	c.14+285G>C		intron	N/A	ENSP00000258148.7	G3XA89
	MDM2	ENST00000890006.1		c.14+285G>C		intron	N/A	ENSP00000560065.1

Frequencies

GnomAD3 genomes AF: 0.0225 AC: 3424 AN: 152054 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.00654

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0230

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0187

Gnomad FIN AF: 0.00850

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0362

Gnomad OTH AF: 0.0186

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

GnomAD4 genome AF: 0.0225 AC: 3423 AN: 152170 Hom.: 63 Cov.: 32 AF XY: 0.0213 AC XY: 1581 AN XY: 74392

African (AFR) AF: 0.00652 AC: 271 AN: 41540

American (AMR) AF: 0.0230 AC: 351 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 102 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.0185 AC: 89 AN: 4818

European-Finnish (FIN) AF: 0.00850 AC: 90 AN: 10594

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.0362 AC: 2464 AN: 67986

Other (OTH) AF: 0.0184 AC: 39 AN: 2116

Alfa AF: 0.0289 Hom.: 10

Bravo AF: 0.0217

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Accelerated tumor formation, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	3.6
DANN	Benign	0.47
PhyloP100		-2.3
PromoterAI		0.0054	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.7
Mutation Taster		=100/0	polymorphism

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: rs117039649; hg19: chr12-69202556; COSMIC: COSV50704574; COSMIC: COSV50704574;