Genetic Variant MDM2:c.-430C>G (chr12-68808048-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002392.6(MDM2):c.-430C>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000741 in 430,236 control chromosomes in the GnomAD database, including 1 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 0.00089 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00066 ( 0 hom. )

Consequence

MDM2
NM_002392.6 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.15

Publications

1 publications found

Variant links:

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)

MDM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BS2

High AC in GnomAd4 at 136 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM2	NM_002392.6 link	c.-430C>G		upstream_gene_variant		ENST00000258149.11	NP_002383.2
MDM2	NM_001145339.2 link	c.-430C>G		upstream_gene_variant			NP_001138811.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein
MDM2	ENST00000258149.11 link	c.-430C>G	upstream_gene_variant	1	NM_002392.6	ENSP00000258149.6
MDM2	ENST00000393412.7 link	c.-448C>G	upstream_gene_variant	5		ENSP00000377064.4
MDM2	ENST00000311420.13 link	n.-430C>G	upstream_gene_variant	5		ENSP00000310742.9
MDM2	ENST00000493419.1 link	n.-234C>G	upstream_gene_variant	2

Frequencies

GnomAD3 genomes

AF:

0.000894

AC:

136

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00379

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00155

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000471

Gnomad OTH

AF:

0.00239

GnomAD4 exome

AF:

0.000658

AC:

183

AN:

278008

Hom.:

AF XY:

0.000685

AC XY:

AN XY:

143166

show subpopulations

African (AFR)

AF:

0.000705

AC:

AN:

7094

American (AMR)

AF:

0.00407

AC:

AN:

7380

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9792

East Asian (EAS)

AF:

0.000132

AC:

AN:

22728

South Asian (SAS)

AF:

0.0000844

AC:

AN:

11848

European-Finnish (FIN)

AF:

0.0000421

AC:

AN:

23736

Middle Eastern (MID)

AF:

0.00430

AC:

AN:

1394

European-Non Finnish (NFE)

AF:

0.000647

AC:

114

AN:

176206

Other (OTH)

AF:

0.00129

AC:

AN:

17830

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000893

AC:

136

AN:

152228

Hom.:

Cov.:

AF XY:

0.000941

AC XY:

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.000746

AC:

AN:

41542

American (AMR)

AF:

0.00379

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00155

AC:

AN:

5160

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000471

AC:

AN:

67982

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000530

Hom.:

Bravo

AF:

0.00140

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.75

(source)

DANN

Benign

0.42

PhyloP100

-4.1

PromoterAI

-0.097

Neutral

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over