Genetic Variant CDC20:p.Arg162Trp (chr1-43360025-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

The NM_001255.3(CDC20):c.484C>T(p.Arg162Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R162G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CDC20
NM_001255.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.00

Publications

0 publications found

Variant links:

Genes affected

CDC20 (HGNC:1723): (cell division cycle 20) CDC20 appears to act as a regulatory protein interacting with several other proteins at multiple points in the cell cycle. It is required for two microtubule-dependent processes, nuclear movement prior to anaphase and chromosome separation. [provided by RefSeq, Jul 2008]

CDC20 Gene-Disease associations (from GenCC):

oocyte maturation defect 14
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

CDC20 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 1.8304 (below the threshold of 3.09). Trascript score misZ: 2.4972 (below the threshold of 3.09). GenCC associations: The gene is linked to oocyte maturation defect 14.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC20	NM_001255.3 link	c.484C>T	p.Arg162Trp	missense_variant	Exon 5 of 11	ENST00000310955.11	NP_001246.2	Q12834

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDC20	ENST00000310955.11 link	c.484C>T	p.Arg162Trp	missense_variant	Exon 5 of 11	1	NM_001255.3	ENSP00000308450.5	Q12834
CDC20	ENST00000372462.1 link	c.484C>T	p.Arg162Trp	missense_variant	Exon 4 of 10	1		ENSP00000361540.1	Q12834
CDC20	ENST00000478882.1 link	n.259C>T		non_coding_transcript_exon_variant	Exon 1 of 4	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251136

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461794

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111950

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;T

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.88

.;D

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.43

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Pathogenic

3.2

M;M

PhyloP100

2.0

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Benign

0.27

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.97

D;D

Vest4

0.40

MutPred

0.58

Loss of catalytic residue at R162 (P = 0.0037);Loss of catalytic residue at R162 (P = 0.0037);

MVP

0.69

MPC

0.67

ClinPred

0.99

GERP RS

2.7

Varity_R

0.49

gMVP

0.51

Mutation Taster

=56/44

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over