rs4135012

Positions:

• chr17-40293996-G-A

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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 8.43

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=0.011202812).
• 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	UniProt
CDC6	NM_001254.4	c.883G>A	p.Asp295Asn	missense_variant	6/12	ENST00000209728.9
CDC6	XM_011525541.3	c.883G>A	p.Asp295Asn	missense_variant	6/13
CDC6	XM_011525542.2	c.883G>A	p.Asp295Asn	missense_variant	6/13
CDC6	XM_047437207.1	c.883G>A	p.Asp295Asn	missense_variant	6/12

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2311 AN: 152200 Hom.: 30 Cov.: 32

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.: 25 AF XY: 0.0138 AC XY: 1870 AN XY: 135914

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.: 32 AF XY: 0.0199 AC XY: 14476 AN XY: 727128

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.: 30 Cov.: 32 AF XY: 0.0154 AC XY: 1150 AN XY: 74494

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.: 69

Bravo AF: 0.0139

TwinsUK AF: 0.0245 AC: 91

ALSPAC AF: 0.0249 AC: 96

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0212 AC: 182

ExAC AF: 0.0131 AC: 1586

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0204

EpiControl AF: 0.0205

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 21, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CDC6: BS1, BS2 -

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	T
BayesDel_noAF	Benign	-0.47
CADD	Pathogenic	28
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	D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.8	L;L;L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
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	T
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

Other links and lift over

dbSNP: rs4135012; hg19: chr17-38450248; COSMIC: COSV99079657; COSMIC: COSV99079657;