rs1130199

Positions:

• chr17-40291317-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001254.4(CDC6):​c.438T>C​(p.Cys146=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,614,116 control chromosomes in the GnomAD database, including 4,577 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (2456 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (2121 hom.)
• Consequence: CDC6 NM_001254.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.340

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-40291317-T-C is Benign according to our data. Variant chr17-40291317-T-C is described in ClinVar as [Benign]. Clinvar id is 128636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDC6	NM_001254.4	c.438T>C	p.Cys146=	synonymous_variant	3/12	ENST00000209728.9
CDC6	XM_011525541.3	c.438T>C	p.Cys146=	synonymous_variant	3/13
CDC6	XM_011525542.2	c.438T>C	p.Cys146=	synonymous_variant	3/13
CDC6	XM_047437207.1	c.438T>C	p.Cys146=	synonymous_variant	3/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDC6	ENST00000209728.9	c.438T>C	p.Cys146=	synonymous_variant	3/12	1	NM_001254.4	P1
CDC6	ENST00000649662.1	c.438T>C	p.Cys146=	synonymous_variant	3/12			P1
CDC6	ENST00000580824.5	c.438T>C	p.Cys146=	synonymous_variant	3/4	3

Frequencies

GnomAD3 genomes AF: 0.0969 AC: 14749 AN: 152140 Hom.: 2441 Cov.: 32

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.0732

GnomAD3 exomes AF: 0.0251 AC: 6307 AN: 251192 Hom.: 954 AF XY: 0.0184 AC XY: 2502 AN XY: 135872

Gnomad AFR exome AF: 0.343

Gnomad AMR exome AF: 0.0167

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000947

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000818

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.00992 AC: 14503 AN: 1461858 Hom.: 2121 Cov.: 33 AF XY: 0.00852 AC XY: 6199 AN XY: 727226

Gnomad4 AFR exome AF: 0.344

Gnomad4 AMR exome AF: 0.0188

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000986

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000486

Gnomad4 OTH exome AF: 0.0230

GnomAD4 genome AF: 0.0972 AC: 14800 AN: 152258 Hom.: 2456 Cov.: 32 AF XY: 0.0946 AC XY: 7040 AN XY: 74450

Gnomad4 AFR AF: 0.339

Gnomad4 AMR AF: 0.0324

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.0724

Alfa AF: 0.0318 Hom.: 887

Bravo AF: 0.110

Asia WGS AF: 0.0220 AC: 78 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.2
DANN	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1130199; hg19: chr17-38447569;