dbSNP rs764112565: CDC6:p.Met263Ile (chr17-40293584-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M263V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CDC6
NM_001254.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.842

Publications

0 publications found

Variant links:

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

CDC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -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 rank	MANE	Protein
CDC6	NM_001254.4 link	c.789G>A	p.Met263Ile	missense_variant	Exon 5 of 12	ENST00000209728.9	NP_001245.1
CDC6	XM_011525541.3 link	c.789G>A	p.Met263Ile	missense_variant	Exon 5 of 13		XP_011523843.1
CDC6	XM_011525542.2 link	c.789G>A	p.Met263Ile	missense_variant	Exon 5 of 13		XP_011523844.1
CDC6	XM_047437207.1 link	c.789G>A	p.Met263Ile	missense_variant	Exon 5 of 12		XP_047293163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CDC6	ENST00000209728.9 link	c.789G>A	p.Met263Ile	missense_variant	Exon 5 of 12	1	NM_001254.4	ENSP00000209728.4
CDC6	ENST00000649662.1 link	c.789G>A	p.Met263Ile	missense_variant	Exon 5 of 12			ENSP00000497345.1
CDC6	ENST00000582402.1 link	n.203-1772G>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461608

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111758

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

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

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

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

LIST_S2

Benign

0.59

.;.;T

M_CAP

Benign

0.0033

MetaRNN

Benign

0.063

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.89

N;N;N

PhyloP100

0.84

PrimateAI

Benign

0.37

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

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over