17-40294009-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.66

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 -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 GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDC6	NM_001254.4	c.896C>T	p.Thr299Met	missense_variant	6/12	ENST00000209728.9
CDC6	XM_011525541.3	c.896C>T	p.Thr299Met	missense_variant	6/13
CDC6	XM_011525542.2	c.896C>T	p.Thr299Met	missense_variant	6/13
CDC6	XM_047437207.1	c.896C>T	p.Thr299Met	missense_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDC6	ENST00000209728.9	c.896C>T	p.Thr299Met	missense_variant	6/12	1	NM_001254.4	P1
CDC6	ENST00000649662.1	c.896C>T	p.Thr299Met	missense_variant	6/12			P1
CDC6	ENST00000582402.1	n.203-1347C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00544 AC: 827 AN: 152142 Hom.: 8 Cov.: 32

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.: 4 AF XY: 0.00132 AC XY: 180 AN XY: 135918

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.: 12 Cov.: 32 AF XY: 0.000613 AC XY: 446 AN XY: 727168

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.: 8 Cov.: 32 AF XY: 0.00527 AC XY: 392 AN XY: 74448

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.: 1

Bravo AF: 0.00587

ESP6500AA AF: 0.0172 AC: 76

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00208 AC: 253

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
Cadd	Pathogenic	27
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	D
MetaRNN	Benign	0.0090	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.0	M;M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
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	T
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

Other links and lift over

dbSNP: rs4135013; hg19: chr17-38450261; COSMIC: COSV52931348; COSMIC: COSV52931348;