Genetic Variant CDT1:p.Ala66Pro (chr16-88804027-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_030928.4(CDT1):c.196G>C(p.Ala66Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000766 in 1,306,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. A66T) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

CDT1
NM_030928.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.713

Publications

0 publications found

Variant links:

Genes affected

CDT1 (HGNC:24576): (chromatin licensing and DNA replication factor 1) The protein encoded by this gene is involved in the formation of the pre-replication complex that is necessary for DNA replication. The encoded protein can bind geminin, which prevents replication and may function to prevent this protein from initiating replication at inappropriate origins. Phosphorylation of this protein by cyclin A-dependent kinases results in degradation of the protein. [provided by RefSeq, Mar 2011]

CDT1 Gene-Disease associations (from GenCC):

Meier-Gorlin syndrome 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
Meier-Gorlin syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CDT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-88804027-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 30501.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.19209662).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDT1	NM_030928.4 link	c.196G>C	p.Ala66Pro	missense_variant	Exon 1 of 10	ENST00000301019.9	NP_112190.2	Q9H211

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDT1	ENST00000301019.9 link	c.196G>C	p.Ala66Pro	missense_variant	Exon 1 of 10	1	NM_030928.4	ENSP00000301019.4		Q9H211

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.66e-7

AC:

AN:

1306248

Hom.:

Cov.:

AF XY:

0.00000155

AC XY:

AN XY:

644362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25914

American (AMR)

AF:

0.00

AC:

AN:

23866

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22560

East Asian (EAS)

AF:

0.00

AC:

AN:

29064

South Asian (SAS)

AF:

0.00

AC:

AN:

70746

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32030

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3854

European-Non Finnish (NFE)

AF:

9.58e-7

AC:

AN:

1044324

Other (OTH)

AF:

0.00

AC:

AN:

53890

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.057

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.53

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.5

PhyloP100

0.71

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.8

REVEL

Benign

0.11

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.017

Polyphen

0.29

Vest4

0.22

MutPred

0.29

Gain of glycosylation at A66 (P = 0.0019);

MVP

0.84

MPC

1.6

ClinPred

0.32

GERP RS

1.6

PromoterAI

-0.023

Neutral

(source)

Varity_R

0.28

gMVP

0.39

Mutation Taster

=74/26

polymorphism

(source)

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

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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