17-40289585-C-T

Position:

chr17-40289585-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001254.4(CDC6):c.165C>T(p.Pro55=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,613,974 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0016 ( 12 hom. )

Consequence

CDC6
NM_001254.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.208

Variant links:

Genes affected

CDC6 (HGNC:1744): (cell division cycle 6) The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Cdc6, a protein essential for the initiation of DNA replication. This protein functions as a regulator at the early steps of DNA replication. It localizes in cell nucleus during cell cyle G1, but translocates to the cytoplasm at the start of S phase. The subcellular translocation of this protein during cell cyle is regulated through its phosphorylation by Cdks. Transcription of this protein was reported to be regulated in response to mitogenic signals through transcriptional control mechanism involving E2F proteins. [provided by RefSeq, Jul 2008]

CDC6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 17-40289585-C-T is Benign according to our data. Variant chr17-40289585-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 210619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-40289585-C-T is described in Lovd as [Benign]. Variant chr17-40289585-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.208 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0016 (2339/1461724) while in subpopulation MID AF= 0.0199 (115/5768). AF 95% confidence interval is 0.017. There are 12 homozygotes in gnomad4_exome. There are 1330 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CDC6	NM_001254.4 linkuse as main transcript	c.165C>T	p.Pro55=	synonymous_variant	2/12	ENST00000209728.9	NP_001245.1
CDC6	XM_011525541.3 linkuse as main transcript	c.165C>T	p.Pro55=	synonymous_variant	2/13		XP_011523843.1
CDC6	XM_011525542.2 linkuse as main transcript	c.165C>T	p.Pro55=	synonymous_variant	2/13		XP_011523844.1
CDC6	XM_047437207.1 linkuse as main transcript	c.165C>T	p.Pro55=	synonymous_variant	2/12		XP_047293163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC6	ENST00000209728.9 linkuse as main transcript	c.165C>T	p.Pro55=	synonymous_variant	2/12	1	NM_001254.4	ENSP00000209728	P1

Frequencies

GnomAD3 genomes

AF:

0.00123

AC:

187

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00148

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00221

AC:

556

AN:

251396

Hom.:

AF XY:

0.00252

AC XY:

342

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00147

Gnomad ASJ exome

AF:

0.00536

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00653

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00200

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00160

AC:

2339

AN:

1461724

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

1330

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.00152

Gnomad4 ASJ exome

AF:

0.00455

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00646

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.00120

Gnomad4 OTH exome

AF:

0.00205

GnomAD4 genome

AF:

0.00122

AC:

185

AN:

152250

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00477

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00148

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00181

Hom.:

Bravo

AF:

0.00127

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00229

EpiControl

AF:

0.00284

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	CDC6: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 06, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Meier-Gorlin syndrome 5

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.75

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over