NM_001254.4:c.1321G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001254.4(CDC6):c.1321G>A(p.Val441Ile) variant causes a missense change. The variant allele was found at a frequency of 0.133 in 1,613,406 control chromosomes in the GnomAD database, including 21,131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 5607 hom., cov: 32)

Exomes 𝑓: 0.12 ( 15524 hom. )

Consequence

CDC6
NM_001254.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.48

Publications

51 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=0.0025324821).

BP6

Variant 17-40300899-G-A is Benign according to our data. Variant chr17-40300899-G-A is described in ClinVar as Benign. ClinVar VariationId is 128635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CDC6	NM_001254.4 link	c.1321G>A	p.Val441Ile	missense_variant	Exon 10 of 12	ENST00000209728.9	NP_001245.1
CDC6	XM_011525541.3 link	c.1441G>A	p.Val481Ile	missense_variant	Exon 11 of 13		XP_011523843.1
CDC6	XM_011525542.2 link	c.1441G>A	p.Val481Ile	missense_variant	Exon 11 of 13		XP_011523844.1
CDC6	XM_047437207.1 link	c.1321G>A	p.Val441Ile	missense_variant	Exon 10 of 12		XP_047293163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CDC6	ENST00000209728.9 link	c.1321G>A	p.Val441Ile	missense_variant	Exon 10 of 12	1	NM_001254.4	ENSP00000209728.4
CDC6	ENST00000649662.1 link	c.1321G>A	p.Val441Ile	missense_variant	Exon 10 of 12			ENSP00000497345.1
CDC6	ENST00000648633.1 link	n.10G>A		non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.219

AC:

33331

AN:

151996

Hom.:

5570

Cov.:

show subpopulations

Gnomad AFR

AF:

0.467

Gnomad AMI

AF:

0.208

Gnomad AMR

AF:

0.153

Gnomad ASJ

AF:

0.0904

Gnomad EAS

AF:

0.353

Gnomad SAS

AF:

0.104

Gnomad FIN

AF:

0.120

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.106

Gnomad OTH

AF:

0.177

GnomAD2 exomes

AF:

0.155

AC:

38850

AN:

251398

AF XY:

0.144

show subpopulations

Gnomad AFR exome

AF:

0.476

Gnomad AMR exome

AF:

0.140

Gnomad ASJ exome

AF:

0.0980

Gnomad EAS exome

AF:

0.353

Gnomad FIN exome

AF:

0.118

Gnomad NFE exome

AF:

0.109

Gnomad OTH exome

AF:

0.131

GnomAD4 exome

AF:

0.124

AC:

181048

AN:

1461292

Hom.:

15524

Cov.:

AF XY:

0.122

AC XY:

88983

AN XY:

726980

show subpopulations

African (AFR)

AF:

0.475

AC:

15908

AN:

33466

American (AMR)

AF:

0.145

AC:

6468

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0986

AC:

2577

AN:

26126

East Asian (EAS)

AF:

0.397

AC:

15745

AN:

39694

South Asian (SAS)

AF:

0.100

AC:

8637

AN:

86250

European-Finnish (FIN)

AF:

0.116

AC:

6190

AN:

53420

Middle Eastern (MID)

AF:

0.121

AC:

699

AN:

5766

European-Non Finnish (NFE)

AF:

0.105

AC:

116245

AN:

1111476

Other (OTH)

AF:

0.142

AC:

8579

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

7969

15938

23907

31876

39845

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4548

9096

13644

18192

22740

<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:

0.220

AC:

33428

AN:

152114

Hom.:

5607

Cov.:

AF XY:

0.219

AC XY:

16266

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.468

AC:

19380

AN:

41424

American (AMR)

AF:

0.153

AC:

2347

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0904

AC:

314

AN:

3472

East Asian (EAS)

AF:

0.353

AC:

1828

AN:

5180

South Asian (SAS)

AF:

0.105

AC:

506

AN:

4830

European-Finnish (FIN)

AF:

0.120

AC:

1277

AN:

10604

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.106

AC:

7178

AN:

68000

Other (OTH)

AF:

0.176

AC:

372

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1145

2291

3436

4582

5727

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

322

644

966

1288

1610

<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:

0.149

Hom.:

11993

Bravo

AF:

0.236

TwinsUK

AF:

0.0979

AC:

363

ALSPAC

AF:

0.107

AC:

411

ESP6500AA

AF:

0.457

AC:

2014

ESP6500EA

AF:

0.110

AC:

950

ExAC

AF:

0.159

AC:

19246

Asia WGS

AF:

0.236

AC:

819

AN:

3478

EpiCase

AF:

0.112

EpiControl

AF:

0.111

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17000706, 19233139) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Meier-Gorlin syndrome 5

Benign:2

Mar 06, 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. -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.035

T;T;T

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.79

.;.;T

MetaRNN

Benign

0.0025

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.0

M;M;M

PhyloP100

4.5

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.90

N;.;.

REVEL

Benign

0.10

Sift

Uncertain

0.023

D;.;.

Sift4G

Uncertain

0.019

D;.;.

Polyphen

0.84

P;P;P

Vest4

0.021

MPC

0.28

ClinPred

0.022

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.078

gMVP

0.23

Mutation Taster

=93/7

polymorphism (auto)

(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