rs142289528

chr17-40289585-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.208

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]

ACMG classification

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 GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDC6	NM_001254.4	c.165C>T	p.Pro55=	synonymous_variant	2/12	ENST00000209728.9
CDC6	XM_011525541.3	c.165C>T	p.Pro55=	synonymous_variant	2/13
CDC6	XM_011525542.2	c.165C>T	p.Pro55=	synonymous_variant	2/13
CDC6	XM_047437207.1	c.165C>T	p.Pro55=	synonymous_variant	2/12

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 187 AN: 152132 Hom.: 3 Cov.: 31

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.: 3 AF XY: 0.00252 AC XY: 342 AN XY: 135890

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.: 12 Cov.: 31 AF XY: 0.00183 AC XY: 1330 AN XY: 727170

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.: 3 Cov.: 31 AF XY: 0.00121 AC XY: 90 AN XY: 74452

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.: 1

Bravo AF: 0.00127

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00229

EpiControl AF: 0.00284

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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	12
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

Other links and lift over

dbSNP: rs142289528; hg19: chr17-38445837;