chr12-68830162-A-G

Variant names:

• chr12-68830162-A-G
• rs1695144
• NM_002392.6:c.684+1231A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_002392.6(MDM2):​c.684+1231A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 152,058 control chromosomes in the GnomAD database, including 36 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 0.018 (36 hom., cov: 32)
• Consequence: MDM2 NM_002392.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.132
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0182 (2774/152058) while in subpopulation AFR AF = 0.0283 (1174/41442). AF 95% confidence interval is 0.027. There are 36 homozygotes in GnomAd4. There are 1323 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2774 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM2	NM_002392.6	MANE Select	c.684+1231A>G		intron	N/A	NP_002383.2
	MDM2	NM_001367990.1		c.666+1231A>G		intron	N/A	NP_001354919.1
	MDM2	NM_001145337.3		c.666+1231A>G		intron	N/A	NP_001138809.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM2	ENST00000258149.11	TSL:1 MANE Select	c.684+1231A>G		intron	N/A	ENSP00000258149.6
	MDM2	ENST00000539479.6	TSL:1	c.666+1231A>G		intron	N/A	ENSP00000444430.2
	MDM2	ENST00000350057.9	TSL:1	c.591+1231A>G		intron	N/A	ENSP00000266624.9

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2768 AN: 151940 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0283

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: 0.0223

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.0158

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

GnomAD4 genome AF: 0.0182 AC: 2774 AN: 152058 Hom.: 36 Cov.: 32 AF XY: 0.0178 AC XY: 1323 AN XY: 74320

African (AFR) AF: 0.0283 AC: 1174 AN: 41442

American (AMR) AF: 0.0108 AC: 165 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00540 AC: 26 AN: 4816

European-Finnish (FIN) AF: 0.0223 AC: 235 AN: 10550

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0163 AC: 1112 AN: 68024

Other (OTH) AF: 0.0157 AC: 33 AN: 2106

Alfa AF: 0.0154 Hom.: 33

Bravo AF: 0.0186

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.4
DANN	Benign	0.53
PhyloP100		-0.13
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: rs1695144; hg19: chr12-69223942;