rs480727

chr16-88805821-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (20328 hom., cov: 34)
  • Exomes 𝑓: 0.39 (119607 hom.)
• Consequence: CDT1 NM_030928.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.464

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 128682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88805821-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDT1	NM_030928.4	c.784A>G	p.Thr262Ala	missense_variant	5/10	ENST00000301019.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDT1	ENST00000301019.9	c.784A>G	p.Thr262Ala	missense_variant	5/10	1	NM_030928.4	P1
CDT1	ENST00000569140.1	c.55A>G	p.Thr19Ala	missense_variant	1/5	3
CDT1	ENST00000562747.1	n.490A>G		non_coding_transcript_exon_variant	4/5	2

Frequencies

GnomAD3 genomes AF: 0.495 AC: 75285 AN: 151988 Hom.: 20293 Cov.: 34

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

GnomAD3 exomes AF: 0.442 AC: 109875 AN: 248612 Hom.: 26065 AF XY: 0.435 AC XY: 58633 AN XY: 134908

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 SAS exome AF: 0.419

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.: 65 AF XY: 0.395 AC XY: 287245 AN XY: 726404

Gnomad4 AFR exome AF: 0.725

Gnomad4 AMR exome AF: 0.445

Gnomad4 ASJ exome AF: 0.523

Gnomad4 EAS exome AF: 0.735

Gnomad4 SAS exome AF: 0.417

Gnomad4 FIN exome AF: 0.342

Gnomad4 NFE exome AF: 0.365

Gnomad4 OTH exome AF: 0.438

GnomAD4 genome AF: 0.495 AC: 75367 AN: 152104 Hom.: 20328 Cov.: 34 AF XY: 0.493 AC XY: 36673 AN XY: 74346

Gnomad4 AFR AF: 0.705

Gnomad4 AMR AF: 0.472

Gnomad4 ASJ AF: 0.527

Gnomad4 EAS AF: 0.719

Gnomad4 SAS AF: 0.417

Gnomad4 FIN AF: 0.344

Gnomad4 NFE AF: 0.382

Gnomad4 OTH AF: 0.520

Alfa AF: 0.414 Hom.: 27209

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

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Meier-Gorlin syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.69
Dann	Benign	0.43
DEOGEN2	Benign	0.031	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.029	T
MetaRNN	Benign	0.0000018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.080	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.0060
Sift	Benign	0.72	T
Sift4G	Benign	0.84	T
Polyphen		0.0030	B
Vest4		0.012
MPC		0.013
ClinPred		0.0017	T
GERP RS		-1.3
Varity_R		0.024
gMVP		0.30

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

LitVar

Other links and lift over

dbSNP: rs480727; hg19: chr16-88872229; COSMIC: COSV56349614; COSMIC: COSV56349614;