Genetic Variant MDM2:c.-430C>T (chr12-68808048-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_002392.6(MDM2):c.-430C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 430,234 control chromosomes in the GnomAD database, including 6 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 0.0010 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 5 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00101 (154/152228) while in subpopulation EAS AF = 0.0234 (121/5160). AF 95% confidence interval is 0.0201. There are 1 homozygotes in GnomAd4. There are 80 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 154 AD,Unknown gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

156

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0238

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000955

GnomAD4 exome

AF:

0.00102

AC:

283

AN:

278006

Hom.:

AF XY:

0.00106

AC XY:

152

AN XY:

143164

show subpopulations

African (AFR)

AF:

0.000282

AC:

AN:

7094

American (AMR)

AF:

0.000271

AC:

AN:

7380

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9792

East Asian (EAS)

AF:

0.00849

AC:

193

AN:

22728

South Asian (SAS)

AF:

0.000338

AC:

AN:

11848

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23736

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1394

European-Non Finnish (NFE)

AF:

0.0000227

AC:

AN:

176206

Other (OTH)

AF:

0.00438

AC:

AN:

17828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00101

AC:

154

AN:

152228

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.000506

AC:

AN:

41542

American (AMR)

AF:

0.000261

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0234

AC:

121

AN:

5160

South Asian (SAS)

AF:

0.00104

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:

0.0000147

AC:

AN:

67982

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00

Hom.:

Bravo

AF:

0.00129

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

2.1

(source)

DANN

Benign

0.89

PhyloP100

-4.1

PromoterAI

-0.057

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