16-88804016-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030928.4(CDT1):c.185C>T(p.Ala62Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00352 in 1,463,926 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A62T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0073 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (76 hom.)
• Consequence: CDT1 NM_030928.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.86

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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_030928.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0029655993).
• BP6: Variant 16-88804016-C-T is Benign according to our data. Variant chr16-88804016-C-T is described in ClinVar as [Benign]. Clinvar id is 434671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00725 (1102/151980) while in subpopulation EAS AF= 0.0199 (103/5168). AF 95% confidence interval is 0.0168. There are 34 homozygotes in gnomad4. There are 793 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDT1	NM_030928.4	c.185C>T	p.Ala62Val	missense_variant	1/10	ENST00000301019.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDT1	ENST00000301019.9	c.185C>T	p.Ala62Val	missense_variant	1/10	1	NM_030928.4	P1

Frequencies

GnomAD3 genomes AF: 0.00725 AC: 1101 AN: 151872 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00845

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.0201

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0685

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00670 AC: 522 AN: 77870 Hom.: 12 AF XY: 0.00527 AC XY: 237 AN XY: 44988

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00684

Gnomad ASJ exome AF: 0.00171

Gnomad EAS exome AF: 0.0218

Gnomad SAS exome AF: 0.00193

Gnomad FIN exome AF: 0.0551

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.00390

GnomAD4 exome AF: 0.00309 AC: 4055 AN: 1311946 Hom.: 76 Cov.: 31 AF XY: 0.00297 AC XY: 1921 AN XY: 647274

Gnomad4 AFR exome AF: 0.0000764

Gnomad4 AMR exome AF: 0.00737

Gnomad4 ASJ exome AF: 0.00132

Gnomad4 EAS exome AF: 0.0381

Gnomad4 SAS exome AF: 0.00217

Gnomad4 FIN exome AF: 0.0500

Gnomad4 NFE exome AF: 0.000718

Gnomad4 OTH exome AF: 0.00388

GnomAD4 genome AF: 0.00725 AC: 1102 AN: 151980 Hom.: 34 Cov.: 32 AF XY: 0.0107 AC XY: 793 AN XY: 74252

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00877

Gnomad4 ASJ AF: 0.00116

Gnomad4 EAS AF: 0.0199

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0685

Gnomad4 NFE AF: 0.00162

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00230 Hom.: 0

Bravo AF: 0.00309

ExAC AF: 0.00212 AC: 31

Asia WGS AF: 0.0130 AC: 42 AN: 3332

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.016
Sift	Benign	0.28	T
Sift4G	Benign	0.30	T
Polyphen		0.063	B
Vest4		0.081
MVP		0.79
MPC		1.2
ClinPred		0.019	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.039
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs561655241; hg19: chr16-88870424; COSMIC: COSV56349425; COSMIC: COSV56349425;