rs2306392

Variant names:

• chr12-68313507-G-A
• rs2306392
• NM_001354969.2:c.1685C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-68313507-G-A
• chr12-68313507-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001354969.2(MDM1):​c.1685C>T​(p.Pro562Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 1,611,628 control chromosomes in the GnomAD database, including 72,222 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.24 (4812 hom., cov: 32)
  • Exomes 𝑓: 0.30 (67410 hom.)
• Consequence: MDM1 NM_001354969.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.10
• Publications: 33 publications found

Genes affected

MDM1 (HGNC:29917): (Mdm1 nuclear protein) This gene encodes a microtubule-binding nuclear protein that localizes to the centrioles of dividing cells and differentiating multiciliated cells and negatively regulates centriole duplication. The encoded protein is closely associated with the centriole barrel, and resides in the centriole lumen. Naturally-occurring mutations in the orthologous mouse gene are associated with age-related retinal degeneration. [provided by RefSeq, Feb 2019]

MDM1 Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005428165).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354969.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM1	NM_001354969.2	MANE Select	c.1685C>T	p.Pro562Leu	missense	Exon 12 of 15	NP_001341898.1	A0A804HIJ5
	MDM1	NM_017440.6		c.1655C>T	p.Pro552Leu	missense	Exon 11 of 14	NP_059136.2	Q8TC05-1
	MDM1	NM_001205028.3		c.1550C>T	p.Pro517Leu	missense	Exon 11 of 14	NP_001191957.1	Q8TC05-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM1	ENST00000682720.1	MANE Select	c.1685C>T	p.Pro562Leu	missense	Exon 12 of 15	ENSP00000507100.1	A0A804HIJ5
	MDM1	ENST00000303145.11	TSL:1	c.1655C>T	p.Pro552Leu	missense	Exon 11 of 14	ENSP00000302537.7	Q8TC05-1
	MDM1	ENST00000540418.5	TSL:1	n.*1149C>T		non_coding_transcript_exon	Exon 10 of 13	ENSP00000443815.2	F5H804

Frequencies

GnomAD3 genomes AF: 0.237 AC: 35956 AN: 151990 Hom.: 4816 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.282

GnomAD2 exomes AF: 0.272 AC: 68261 AN: 251250 AF XY: 0.285

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.197

Gnomad ASJ exome AF: 0.388

Gnomad EAS exome AF: 0.158

Gnomad FIN exome AF: 0.193

Gnomad NFE exome AF: 0.312

Gnomad OTH exome AF: 0.306

GnomAD4 exome AF: 0.298 AC: 435356 AN: 1459518 Hom.: 67410 Cov.: 33 AF XY: 0.302 AC XY: 219250 AN XY: 726150

African (AFR) AF: 0.111 AC: 3714 AN: 33458

American (AMR) AF: 0.203 AC: 9058 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.380 AC: 9919 AN: 26110

East Asian (EAS) AF: 0.187 AC: 7412 AN: 39690

South Asian (SAS) AF: 0.364 AC: 31368 AN: 86158

European-Finnish (FIN) AF: 0.201 AC: 10749 AN: 53408

Middle Eastern (MID) AF: 0.419 AC: 2413 AN: 5760

European-Non Finnish (NFE) AF: 0.308 AC: 342342 AN: 1109950

Other (OTH) AF: 0.305 AC: 18381 AN: 60298

GnomAD4 genome AF: 0.236 AC: 35961 AN: 152110 Hom.: 4812 Cov.: 32 AF XY: 0.232 AC XY: 17267 AN XY: 74370

African (AFR) AF: 0.116 AC: 4832 AN: 41486

American (AMR) AF: 0.256 AC: 3922 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 1368 AN: 3468

East Asian (EAS) AF: 0.173 AC: 897 AN: 5178

South Asian (SAS) AF: 0.346 AC: 1664 AN: 4814

European-Finnish (FIN) AF: 0.176 AC: 1868 AN: 10588

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.302 AC: 20498 AN: 67964

Other (OTH) AF: 0.284 AC: 602 AN: 2116

Alfa AF: 0.292 Hom.: 33991

Bravo AF: 0.234

TwinsUK AF: 0.311 AC: 1155

ALSPAC AF: 0.306 AC: 1181

ESP6500AA AF: 0.126 AC: 557

ESP6500EA AF: 0.313 AC: 2693

ExAC AF: 0.275 AC: 33352

Asia WGS AF: 0.273 AC: 955 AN: 3478

EpiCase AF: 0.327

EpiControl AF: 0.326

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	18
DANN	Benign	0.23
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.99	L
PhyloP100		3.1
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.12
Sift	Benign	0.47	T
Sift4G	Benign	0.34	T
Polyphen		0.0030	B
Vest4		0.032
MPC		0.048
ClinPred		0.016	T
GERP RS		2.2
Varity_R		0.028
gMVP		0.098
Mutation Taster		=98/2	polymorphism (auto)

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: rs2306392; hg19: chr12-68707287; COSMIC: COSV57444838; COSMIC: COSV57444838;