rs510862

Positions:

• chr16-88806103-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_030928.4(CDT1):​c.915T>C​(p.His305=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 1,598,186 control chromosomes in the GnomAD database, including 508,881 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (54038 hom., cov: 35)
  • Exomes 𝑓: 0.79 (454843 hom.)
• Consequence: CDT1 NM_030928.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.92

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 16-88806103-T-C is Benign according to our data. Variant chr16-88806103-T-C is described in ClinVar as [Benign]. Clinvar id is 128683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88806103-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.92 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.951 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDT1	NM_030928.4	c.915T>C	p.His305=	synonymous_variant	6/10	ENST00000301019.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDT1	ENST00000301019.9	c.915T>C	p.His305=	synonymous_variant	6/10	1	NM_030928.4	P1
CDT1	ENST00000569140.1	c.186T>C	p.His62=	synonymous_variant	2/5	3
CDT1	ENST00000562747.1	n.621T>C		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.839 AC: 127616 AN: 152128 Hom.: 53983 Cov.: 35

Gnomad AFR AF: 0.959

Gnomad AMI AF: 0.858

Gnomad AMR AF: 0.769

Gnomad ASJ AF: 0.868

Gnomad EAS AF: 0.899

Gnomad SAS AF: 0.857

Gnomad FIN AF: 0.750

Gnomad MID AF: 0.870

Gnomad NFE AF: 0.788

Gnomad OTH AF: 0.832

GnomAD3 exomes AF: 0.801 AC: 181848 AN: 227080 Hom.: 73454 AF XY: 0.804 AC XY: 99814 AN XY: 124128

Gnomad AFR exome AF: 0.962

Gnomad AMR exome AF: 0.679

Gnomad ASJ exome AF: 0.866

Gnomad EAS exome AF: 0.896

Gnomad SAS exome AF: 0.846

Gnomad FIN exome AF: 0.741

Gnomad NFE exome AF: 0.790

Gnomad OTH exome AF: 0.801

GnomAD4 exome AF: 0.792 AC: 1144914 AN: 1445940 Hom.: 454843 Cov.: 55 AF XY: 0.794 AC XY: 570749 AN XY: 718954

Gnomad4 AFR exome AF: 0.968

Gnomad4 AMR exome AF: 0.694

Gnomad4 ASJ exome AF: 0.868

Gnomad4 EAS exome AF: 0.888

Gnomad4 SAS exome AF: 0.846

Gnomad4 FIN exome AF: 0.753

Gnomad4 NFE exome AF: 0.781

Gnomad4 OTH exome AF: 0.807

GnomAD4 genome AF: 0.839 AC: 127726 AN: 152246 Hom.: 54038 Cov.: 35 AF XY: 0.835 AC XY: 62185 AN XY: 74430

Gnomad4 AFR AF: 0.959

Gnomad4 AMR AF: 0.769

Gnomad4 ASJ AF: 0.868

Gnomad4 EAS AF: 0.899

Gnomad4 SAS AF: 0.859

Gnomad4 FIN AF: 0.750

Gnomad4 NFE AF: 0.788

Gnomad4 OTH AF: 0.831

Alfa AF: 0.803 Hom.: 63347

Bravo AF: 0.844

Asia WGS AF: 0.869 AC: 3023 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

Meier-Gorlin syndrome 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.014
DANN	Benign	0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs510862; hg19: chr16-88872511; COSMIC: COSV56347265; COSMIC: COSV56347265;