rs56410897

chr12-68813544-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002392.6(MDM2):c.100-10C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,603,882 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0058 (14 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (9 hom.)
• Consequence: MDM2 NM_002392.6 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.002388
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.64

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 12-68813544-C-A is Benign according to our data. Variant chr12-68813544-C-A is described in ClinVar as [Benign]. Clinvar id is 472748.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00585 (890/152236) while in subpopulation AFR AF= 0.0208 (862/41538). AF 95% confidence interval is 0.0196. There are 14 homozygotes in gnomad4. There are 398 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDM2	NM_002392.6	c.100-10C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000258149.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDM2	ENST00000258149.11	c.100-10C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002392.6

Frequencies

GnomAD3 genomes AF: 0.00580 AC: 882 AN: 152118 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000918

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00143 AC: 352 AN: 246662 Hom.: 3 AF XY: 0.00108 AC XY: 144 AN XY: 133906

Gnomad AFR exome AF: 0.0215

Gnomad AMR exome AF: 0.000416

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000669

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000334

GnomAD4 exome AF: 0.000593 AC: 861 AN: 1451646 Hom.: 9 Cov.: 28 AF XY: 0.000523 AC XY: 378 AN XY: 722652

Gnomad4 AFR exome AF: 0.0219

Gnomad4 AMR exome AF: 0.000524

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000586

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000172

Gnomad4 OTH exome AF: 0.00143

GnomAD4 genome AF: 0.00585 AC: 890 AN: 152236 Hom.: 14 Cov.: 33 AF XY: 0.00535 AC XY: 398 AN XY: 74430

Gnomad4 AFR AF: 0.0208

Gnomad4 AMR AF: 0.000917

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00463 Hom.: 0

Bravo AF: 0.00676

Asia WGS AF: 0.00260 AC: 9 AN: 3476

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

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	12
Dann	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0024
dbscSNV1_RF	Benign	0.088
SpliceAI score (max)		0.080		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: rs56410897; hg19: chr12-69207324; COSMIC: COSV104573033; COSMIC: COSV104573033;