NM_030928.4:c.1367A>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_030928.4(CDT1):c.1367A>C(p.Glu456Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00173 in 1,612,664 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E456Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0061 ( 10 hom., cov: 34)

Exomes 𝑓: 0.0013 ( 21 hom. )

Consequence

CDT1
NM_030928.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 5.55

Publications

5 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009843707).

BP6

Variant 16-88807372-A-C is Benign according to our data. Variant chr16-88807372-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00606 (924/152364) while in subpopulation AFR AF = 0.0195 (809/41588). AF 95% confidence interval is 0.0183. There are 10 homozygotes in GnomAd4. There are 451 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030928.4. 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
	CDT1	NM_030928.4	MANE Select	c.1367A>C	p.Glu456Ala	missense	Exon 9 of 10	NP_112190.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDT1	ENST00000301019.9	TSL:1 MANE Select	c.1367A>C	p.Glu456Ala	missense	Exon 9 of 10	ENSP00000301019.4
CDT1	ENST00000929785.1		c.1367A>C	p.Glu456Ala	missense	Exon 9 of 10	ENSP00000599844.1
CDT1	ENST00000569140.1	TSL:3	c.*30A>C		downstream_gene	N/A	ENSP00000456926.1

Frequencies

GnomAD3 genomes

AF:

0.00595

AC:

906

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0191

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00890

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00573

GnomAD2 exomes

AF:

0.00285

AC:

706

AN:

247288

AF XY:

0.00303

show subpopulations

Gnomad AFR exome

AF:

0.0201

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000630

Gnomad OTH exome

AF:

0.00183

GnomAD4 exome

AF:

0.00128

AC:

1871

AN:

1460300

Hom.:

Cov.:

AF XY:

0.00150

AC XY:

1087

AN XY:

726474

show subpopulations

African (AFR)

AF:

0.0205

AC:

687

AN:

33474

American (AMR)

AF:

0.00148

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.0101

AC:

869

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52036

Middle Eastern (MID)

AF:

0.00382

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000468

AC:

AN:

1111926

Other (OTH)

AF:

0.00288

AC:

174

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

141

282

424

565

706

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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

AF:

0.00606

AC:

924

AN:

152364

Hom.:

Cov.:

AF XY:

0.00605

AC XY:

451

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.0195

AC:

809

AN:

41588

American (AMR)

AF:

0.00359

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00870

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68036

Other (OTH)

AF:

0.00567

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

147

196

245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00259

Hom.:

Bravo

AF:

0.00665

ESP6500AA

AF:

0.0198

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00352

AC:

426

Asia WGS

AF:

0.00953

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.45

Eigen

Benign

0.16

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0098

MetaSVM

Benign

-0.48

MutationAssessor

Uncertain

2.4

PhyloP100

5.6

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.37

Sift

Benign

0.097

Sift4G

Benign

0.14

Polyphen

0.72

Vest4

0.55

MVP

0.91

MPC

0.057

ClinPred

0.049

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.28

gMVP

0.47

Mutation Taster

=90/10

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over