17-40294009-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001254.4(CDC6):c.896C>T(p.Thr299Met) variant causes a missense change. The variant allele was found at a frequency of 0.00114 in 1,613,968 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T299T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0054 ( 8 hom., cov: 32)

Exomes 𝑓: 0.00069 ( 12 hom. )

Consequence

CDC6
NM_001254.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 6.66

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

Meier-Gorlin syndrome 5
Inheritance: Unknown, AR Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
Meier-Gorlin syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CDC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0090097785).

BP6

Variant 17-40294009-C-T is Benign according to our data. Variant chr17-40294009-C-T is described in ClinVar as Benign. ClinVar VariationId is 128639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00544 (828/152260) while in subpopulation AFR AF = 0.019 (787/41528). AF 95% confidence interval is 0.0179. There are 8 homozygotes in GnomAd4. There are 392 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AD,Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC6	NM_001254.4 link	c.896C>T	p.Thr299Met	missense_variant	Exon 6 of 12	ENST00000209728.9	NP_001245.1	Q99741A0A024R1S2
CDC6	XM_011525541.3 link	c.896C>T	p.Thr299Met	missense_variant	Exon 6 of 13		XP_011523843.1
CDC6	XM_011525542.2 link	c.896C>T	p.Thr299Met	missense_variant	Exon 6 of 13		XP_011523844.1
CDC6	XM_047437207.1 link	c.896C>T	p.Thr299Met	missense_variant	Exon 6 of 12		XP_047293163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDC6	ENST00000209728.9 link	c.896C>T	p.Thr299Met	missense_variant	Exon 6 of 12	1	NM_001254.4	ENSP00000209728.4	Q99741
CDC6	ENST00000649662.1 link	c.896C>T	p.Thr299Met	missense_variant	Exon 6 of 12			ENSP00000497345.1	Q99741
CDC6	ENST00000582402.1 link	n.203-1347C>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.00544

AC:

827

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0189

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00178

AC:

447

AN:

251478

AF XY:

0.00132

show subpopulations

Gnomad AFR exome

AF:

0.0198

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00304

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000691

AC:

1010

AN:

1461708

Hom.:

Cov.:

AF XY:

0.000613

AC XY:

446

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.0208

AC:

698

AN:

33478

American (AMR)

AF:

0.00152

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00169

AC:

AN:

39688

South Asian (SAS)

AF:

0.000209

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000675

AC:

AN:

1111858

Other (OTH)

AF:

0.00129

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

108

163

217

271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00544

AC:

828

AN:

152260

Hom.:

Cov.:

AF XY:

0.00527

AC XY:

392

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0190

AC:

787

AN:

41528

American (AMR)

AF:

0.00137

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00116

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68020

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

122

163

204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00155

Hom.:

Bravo

AF:

0.00587

ESP6500AA

AF:

0.0172

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00208

AC:

253

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Jul 06, 2015

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Meier-Gorlin syndrome 5

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.13

T;T;T

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

.;.;D

MetaRNN

Benign

0.0090

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.0

M;M;M

PhyloP100

6.7

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-4.8

D;.;.

REVEL

Benign

0.23

Sift

Uncertain

0.0010

D;.;.

Sift4G

Uncertain

0.0020

D;.;.

Polyphen

1.0

D;D;D

Vest4

0.83

MVP

0.70

MPC

0.75

ClinPred

0.038

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.83

gMVP

0.66

Mutation Taster

=68/32

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over