rs764112565

Positions:

• chr17-40293584-G-A
• chr17-40293584-G-C

Variant summary

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

The NM_001254.4(CDC6):​c.789G>A​(p.Met263Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDC6 NM_001254.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.842

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=0.06297904).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC6	NM_001254.4	c.789G>A	p.Met263Ile	missense_variant	5/12	ENST00000209728.9	NP_001245.1
CDC6	XM_011525541.3	c.789G>A	p.Met263Ile	missense_variant	5/13		XP_011523843.1
CDC6	XM_011525542.2	c.789G>A	p.Met263Ile	missense_variant	5/13		XP_011523844.1
CDC6	XM_047437207.1	c.789G>A	p.Met263Ile	missense_variant	5/12		XP_047293163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC6	ENST00000209728.9	c.789G>A	p.Met263Ile	missense_variant	5/12	1	NM_001254.4	ENSP00000209728	P1
CDC6	ENST00000649662.1	c.789G>A	p.Met263Ile	missense_variant	5/12			ENSP00000497345	P1
CDC6	ENST00000582402.1	n.203-1772G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461608 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.017	T;T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.59	.;.;T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.063	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.89	N;N;N
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.71	N;.;.
REVEL	Benign	0.038
Sift	Benign	0.40	T;.;.
Sift4G	Benign	0.40	T;.;.
Polyphen		0.0010	B;B;B
Vest4		0.084
MutPred		0.27		Loss of ubiquitination at K261 (P = 0.0705);Loss of ubiquitination at K261 (P = 0.0705);Loss of ubiquitination at K261 (P = 0.0705);
MVP		0.49
MPC		0.21
ClinPred		0.29	T
GERP RS		4.2
Varity_R		0.084
gMVP		0.44

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: rs764112565; hg19: chr17-38449836; COSMIC: COSV99266716; COSMIC: COSV99266716;