17-40289491-A-G

Position:

• chr17-40289491-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001254.4(CDC6):​c.71A>G​(p.Asn24Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDC6 NM_001254.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.913

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027885288).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC6	NM_001254.4	c.71A>G	p.Asn24Ser	missense_variant	2/12	ENST00000209728.9	NP_001245.1
CDC6	XM_011525541.3	c.71A>G	p.Asn24Ser	missense_variant	2/13		XP_011523843.1
CDC6	XM_011525542.2	c.71A>G	p.Asn24Ser	missense_variant	2/13		XP_011523844.1
CDC6	XM_047437207.1	c.71A>G	p.Asn24Ser	missense_variant	2/12		XP_047293163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC6	ENST00000209728.9	c.71A>G	p.Asn24Ser	missense_variant	2/12	1	NM_001254.4	ENSP00000209728	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 22, 2020

This variant has not been reported in the literature in individuals with CDC6-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with serine at codon 24 of the CDC6 protein (p.Asn24Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.13
DANN	Benign	0.15
DEOGEN2	Benign	0.012	T;T;T;T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0083	N
LIST_S2	Benign	0.65	.;.;T;T;T;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.028	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.060	N;N;.;.;N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.45	N;.;.;.;.;.
REVEL	Benign	0.053
Sift	Benign	1.0	T;.;.;.;.;.
Sift4G	Benign	0.95	T;.;T;T;.;T
Polyphen		0.0	B;B;.;.;B;.
Vest4		0.044
MutPred		0.16		Gain of phosphorylation at N24 (P = 0.0033);Gain of phosphorylation at N24 (P = 0.0033);Gain of phosphorylation at N24 (P = 0.0033);Gain of phosphorylation at N24 (P = 0.0033);Gain of phosphorylation at N24 (P = 0.0033);Gain of phosphorylation at N24 (P = 0.0033);
MVP		0.33
MPC		0.15
ClinPred		0.031	T
GERP RS		-0.52
Varity_R		0.039
gMVP		0.069

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-38445743;