rs480727

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_030928.4(CDT1):c.784A>G(p.Thr262Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 1,612,382 control chromosomes in the GnomAD database, including 139,935 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.50 ( 20328 hom., cov: 34)

Exomes 𝑓: 0.39 ( 119607 hom. )

Consequence

CDT1
NM_030928.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.464

Publications

45 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=1.8148388E-6).

BP6

Variant 16-88805821-A-G is Benign according to our data. Variant chr16-88805821-A-G is described in ClinVar as Benign. ClinVar VariationId is 128682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

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.784A>G	p.Thr262Ala	missense	Exon 5 of 10	NP_112190.2	Q9H211

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDT1	ENST00000301019.9	TSL:1 MANE Select	c.784A>G	p.Thr262Ala	missense	Exon 5 of 10	ENSP00000301019.4	Q9H211
CDT1	ENST00000929785.1		c.784A>G	p.Thr262Ala	missense	Exon 5 of 10	ENSP00000599844.1
CDT1	ENST00000569140.1	TSL:3	c.52A>G	p.Thr18Ala	missense	Exon 1 of 5	ENSP00000456926.1	H3BSY1

Frequencies

GnomAD3 genomes

AF:

0.495

AC:

75285

AN:

151988

Hom.:

20293

Cov.:

show subpopulations

Gnomad AFR

AF:

0.705

Gnomad AMI

AF:

0.492

Gnomad AMR

AF:

0.472

Gnomad ASJ

AF:

0.527

Gnomad EAS

AF:

0.719

Gnomad SAS

AF:

0.417

Gnomad FIN

AF:

0.344

Gnomad MID

AF:

0.636

Gnomad NFE

AF:

0.382

Gnomad OTH

AF:

0.525

GnomAD2 exomes

AF:

0.442

AC:

109875

AN:

248612

AF XY:

0.435

show subpopulations

Gnomad AFR exome

AF:

0.710

Gnomad AMR exome

AF:

0.433

Gnomad ASJ exome

AF:

0.524

Gnomad EAS exome

AF:

0.721

Gnomad FIN exome

AF:

0.343

Gnomad NFE exome

AF:

0.379

Gnomad OTH exome

AF:

0.444

GnomAD4 exome

AF:

0.395

AC:

576183

AN:

1460278

Hom.:

119607

Cov.:

AF XY:

0.395

AC XY:

287245

AN XY:

726404

show subpopulations

African (AFR)

AF:

0.725

AC:

24257

AN:

33472

American (AMR)

AF:

0.445

AC:

19835

AN:

44602

Ashkenazi Jewish (ASJ)

AF:

0.523

AC:

13677

AN:

26132

East Asian (EAS)

AF:

0.735

AC:

29161

AN:

39680

South Asian (SAS)

AF:

0.417

AC:

35967

AN:

86218

European-Finnish (FIN)

AF:

0.342

AC:

17931

AN:

52430

Middle Eastern (MID)

AF:

0.552

AC:

3143

AN:

5692

European-Non Finnish (NFE)

AF:

0.365

AC:

405774

AN:

1111698

Other (OTH)

AF:

0.438

AC:

26438

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

23185

46370

69555

92740

115925

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13054

26108

39162

52216

65270

<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:

0.495

AC:

75367

AN:

152104

Hom.:

20328

Cov.:

AF XY:

0.493

AC XY:

36673

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.705

AC:

29257

AN:

41498

American (AMR)

AF:

0.472

AC:

7208

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.527

AC:

1830

AN:

3470

East Asian (EAS)

AF:

0.719

AC:

3714

AN:

5166

South Asian (SAS)

AF:

0.417

AC:

2011

AN:

4818

European-Finnish (FIN)

AF:

0.344

AC:

3645

AN:

10584

Middle Eastern (MID)

AF:

0.646

AC:

190

AN:

294

European-Non Finnish (NFE)

AF:

0.382

AC:

25965

AN:

67968

Other (OTH)

AF:

0.520

AC:

1098

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1888

3775

5663

7550

9438

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

650

1300

1950

2600

3250

<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:

0.426

Hom.:

63833

Bravo

AF:

0.518

TwinsUK

AF:

0.366

AC:

1356

ALSPAC

AF:

0.355

AC:

1367

ESP6500AA

AF:

0.713

AC:

3130

ESP6500EA

AF:

0.384

AC:

3304

ExAC

AF:

0.442

AC:

53552

Asia WGS

AF:

0.574

AC:

1997

AN:

3478

EpiCase

AF:

0.397

EpiControl

AF:

0.407

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Meier-Gorlin syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.69

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.031

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.029

MetaRNN

Benign

0.0000018

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.080

PhyloP100

-0.46

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.41

REVEL

Benign

0.0060

Sift

Benign

0.72

Sift4G

Benign

0.84

Polyphen

0.0030

Vest4

0.012

MPC

0.013

ClinPred

0.0017

GERP RS

-1.3

PromoterAI

0.060

Neutral

(source)

Varity_R

0.024

gMVP

0.30

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over