rs4135012

Positions:

chr17-40293996-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001254.4(CDC6):c.883G>A(p.Asp295Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 1,613,948 control chromosomes in the GnomAD database, including 364 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 30 hom., cov: 32)

Exomes 𝑓: 0.020 ( 334 hom. )

Consequence

CDC6
NM_001254.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 8.43

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011202812).

BP6

Variant 17-40293996-G-A is Benign according to our data. Variant chr17-40293996-G-A is described in ClinVar as [Benign]. Clinvar id is 128638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-40293996-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0152 (2310/152318) while in subpopulation NFE AF= 0.023 (1565/68030). AF 95% confidence interval is 0.0221. There are 30 homozygotes in gnomad4. There are 1150 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CDC6	NM_001254.4 linkuse as main transcript	c.883G>A	p.Asp295Asn	missense_variant	6/12	ENST00000209728.9	NP_001245.1
CDC6	XM_011525541.3 linkuse as main transcript	c.883G>A	p.Asp295Asn	missense_variant	6/13		XP_011523843.1
CDC6	XM_011525542.2 linkuse as main transcript	c.883G>A	p.Asp295Asn	missense_variant	6/13		XP_011523844.1
CDC6	XM_047437207.1 linkuse as main transcript	c.883G>A	p.Asp295Asn	missense_variant	6/12		XP_047293163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CDC6	ENST00000209728.9 linkuse as main transcript	c.883G>A	p.Asp295Asn	missense_variant	6/12	1	NM_001254.4	ENSP00000209728	P1
CDC6	ENST00000649662.1 linkuse as main transcript	c.883G>A	p.Asp295Asn	missense_variant	6/12			ENSP00000497345	P1
CDC6	ENST00000582402.1 linkuse as main transcript	n.203-1360G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0152

AC:

2311

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00369

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0179

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.0230

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0230

Gnomad OTH

AF:

0.0148

GnomAD3 exomes

AF:

0.0138

AC:

3471

AN:

251476

Hom.:

AF XY:

0.0138

AC XY:

1870

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00320

Gnomad AMR exome

AF:

0.00711

Gnomad ASJ exome

AF:

0.00585

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00483

Gnomad FIN exome

AF:

0.0236

Gnomad NFE exome

AF:

0.0207

Gnomad OTH exome

AF:

0.0168

GnomAD4 exome

AF:

0.0203

AC:

29654

AN:

1461630

Hom.:

334

Cov.:

AF XY:

0.0199

AC XY:

14476

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.00311

Gnomad4 AMR exome

AF:

0.00798

Gnomad4 ASJ exome

AF:

0.00597

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00530

Gnomad4 FIN exome

AF:

0.0216

Gnomad4 NFE exome

AF:

0.0236

Gnomad4 OTH exome

AF:

0.0181

GnomAD4 genome

AF:

0.0152

AC:

2310

AN:

152318

Hom.:

Cov.:

AF XY:

0.0154

AC XY:

1150

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00368

Gnomad4 AMR

AF:

0.0178

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00477

Gnomad4 FIN

AF:

0.0230

Gnomad4 NFE

AF:

0.0230

Gnomad4 OTH

AF:

0.0147

Alfa

AF:

0.0190

Hom.:

Bravo

AF:

0.0139

TwinsUK

AF:

0.0245

AC:

ALSPAC

AF:

0.0249

AC:

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.0212

AC:

182

ExAC

AF:

0.0131

AC:

1586

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0204

EpiControl

AF:

0.0205

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 21, 2013	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CDC6: BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Meier-Gorlin syndrome 5

Benign:1

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 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

0.29

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.47

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.050

T;T;T

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

.;.;D

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.8

L;L;L

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.6

D;.;.

REVEL

Benign

0.22

Sift

Uncertain

0.0090

D;.;.

Sift4G

Uncertain

0.059

T;.;.

Polyphen

0.89

P;P;P

Vest4

0.26

MPC

0.69

ClinPred

0.028

GERP RS

6.0

Varity_R

0.61

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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