17-40294009-C-T

Position:

chr17-40294009-C-T

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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

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:

CDC6 (HGNC:):

CDC6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC6	NM_001254.4 linkuse as main transcript	c.896C>T	p.Thr299Met	missense_variant	6/12	ENST00000209728.9	NP_001245.1	Q99741A0A024R1S2
CDC6	XM_011525541.3 linkuse as main transcript	c.896C>T	p.Thr299Met	missense_variant	6/13		XP_011523843.1
CDC6	XM_011525542.2 linkuse as main transcript	c.896C>T	p.Thr299Met	missense_variant	6/13		XP_011523844.1
CDC6	XM_047437207.1 linkuse as main transcript	c.896C>T	p.Thr299Met	missense_variant	6/12		XP_047293163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CDC6	ENST00000209728.9 linkuse as main transcript	c.896C>T	p.Thr299Met	missense_variant	6/12	1	NM_001254.4	ENSP00000209728.4	Q99741
CDC6	ENST00000649662.1 linkuse as main transcript	c.896C>T	p.Thr299Met	missense_variant	6/12			ENSP00000497345.1	Q99741
CDC6	ENST00000582402.1 linkuse as main transcript	n.203-1347C>T		intron_variant		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

GnomAD3 exomes

AF:

0.00178

AC:

447

AN:

251478

Hom.:

AF XY:

0.00132

AC XY:

180

AN XY:

135918

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 SAS exome

AF:

0.000196

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

Gnomad4 AFR exome

AF:

0.0208

Gnomad4 AMR exome

AF:

0.00152

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00169

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000675

Gnomad4 OTH exome

AF:

0.00129

GnomAD4 genome

AF:

0.00544

AC:

828

AN:

152260

Hom.:

Cov.:

AF XY:

0.00527

AC XY:

392

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0190

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000874

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 06, 2015

- -

Meier-Gorlin syndrome 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 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

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

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

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

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