17-40294009-C-A

Variant names:

• chr17-40294009-C-A
• rs4135013
• NM_001254.4:c.896C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001254.4(CDC6):​c.896C>A​(p.Thr299Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T299M) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDC6 NM_001254.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.66
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• Meier-Gorlin syndrome 5

  Inheritance: Unknown, AR Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Meier-Gorlin syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC6	NM_001254.4	c.896C>A	p.Thr299Lys	missense_variant	Exon 6 of 12	ENST00000209728.9	NP_001245.1
CDC6	XM_011525541.3	c.896C>A	p.Thr299Lys	missense_variant	Exon 6 of 13		XP_011523843.1
CDC6	XM_011525542.2	c.896C>A	p.Thr299Lys	missense_variant	Exon 6 of 13		XP_011523844.1
CDC6	XM_047437207.1	c.896C>A	p.Thr299Lys	missense_variant	Exon 6 of 12		XP_047293163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC6	ENST00000209728.9	c.896C>A	p.Thr299Lys	missense_variant	Exon 6 of 12	1	NM_001254.4	ENSP00000209728.4
CDC6	ENST00000649662.1	c.896C>A	p.Thr299Lys	missense_variant	Exon 6 of 12			ENSP00000497345.1
CDC6	ENST00000582402.1	n.203-1347C>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 13

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;.;D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L
PhyloP100		6.7
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.3	D;.;.
REVEL	Uncertain	0.33
Sift	Benign	0.077	T;.;.
Sift4G	Benign	0.064	T;.;.
Polyphen		0.91	P;P;P
Vest4		0.84
MutPred		0.61		Gain of ubiquitination at T299 (P = 0.0267);Gain of ubiquitination at T299 (P = 0.0267);Gain of ubiquitination at T299 (P = 0.0267);
MVP		0.66
MPC		0.75
ClinPred		0.97	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.64
gMVP		0.79

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

Other links and lift over

dbSNP: rs4135013; hg19: chr17-38450261;