rs1795480

chr12-68828854-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_002392.6(MDM2):c.607C>T(p.Leu203=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,613,910 control chromosomes in the GnomAD database, including 225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (35 hom., cov: 32)
  • Exomes 𝑓: 0.015 (190 hom.)
• Consequence: MDM2 NM_002392.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.63

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 12-68828854-C-T is Benign according to our data. Variant chr12-68828854-C-T is described in ClinVar as [Benign]. Clinvar id is 472749.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.63 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0182 (2766/152182) while in subpopulation AFR AF= 0.0282 (1169/41494). AF 95% confidence interval is 0.0268. There are 35 homozygotes in gnomad4. There are 1321 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDM2	NM_002392.6	c.607C>T	p.Leu203=	synonymous_variant	8/11	ENST00000258149.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDM2	ENST00000258149.11	c.607C>T	p.Leu203=	synonymous_variant	8/11	1	NM_002392.6

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2760 AN: 152064 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0220

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0142 AC: 3546 AN: 249424 Hom.: 38 AF XY: 0.0141 AC XY: 1906 AN XY: 135322

Gnomad AFR exome AF: 0.0295

Gnomad AMR exome AF: 0.00620

Gnomad ASJ exome AF: 0.00576

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00360

Gnomad FIN exome AF: 0.0225

Gnomad NFE exome AF: 0.0190

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.0148 AC: 21685 AN: 1461728 Hom.: 190 Cov.: 31 AF XY: 0.0145 AC XY: 10565 AN XY: 727178

Gnomad4 AFR exome AF: 0.0298

Gnomad4 AMR exome AF: 0.00704

Gnomad4 ASJ exome AF: 0.00501

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00405

Gnomad4 FIN exome AF: 0.0217

Gnomad4 NFE exome AF: 0.0160

Gnomad4 OTH exome AF: 0.0147

GnomAD4 genome AF: 0.0182 AC: 2766 AN: 152182 Hom.: 35 Cov.: 32 AF XY: 0.0178 AC XY: 1321 AN XY: 74410

Gnomad4 AFR AF: 0.0282

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.0220

Gnomad4 NFE AF: 0.0163

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.0164 Hom.: 39

Bravo AF: 0.0185

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0171

EpiControl AF: 0.0162

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	11
Dann	Benign	0.89

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: rs1795480; hg19: chr12-69222634; COSMIC: COSV50702801; COSMIC: COSV50702801;