chr17-40289481-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001254.4(CDC6):​c.61C>T​(p.Arg21Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

CDC6
NM_001254.4 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.186
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12519807).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDC6NM_001254.4 linkuse as main transcriptc.61C>T p.Arg21Trp missense_variant 2/12 ENST00000209728.9 NP_001245.1
CDC6XM_011525541.3 linkuse as main transcriptc.61C>T p.Arg21Trp missense_variant 2/13 XP_011523843.1
CDC6XM_011525542.2 linkuse as main transcriptc.61C>T p.Arg21Trp missense_variant 2/13 XP_011523844.1
CDC6XM_047437207.1 linkuse as main transcriptc.61C>T p.Arg21Trp missense_variant 2/12 XP_047293163.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDC6ENST00000209728.9 linkuse as main transcriptc.61C>T p.Arg21Trp missense_variant 2/121 NM_001254.4 ENSP00000209728 P1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151988
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000945
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251488
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000103
AC:
15
AN:
1461828
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
8
AN XY:
727214
show subpopulations
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:
0.0000696
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151988
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74206
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000945
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 30, 2021The c.61C>T (p.R21W) alteration is located in exon 2 (coding exon 1) of the CDC6 gene. This alteration results from a C to T substitution at nucleotide position 61, causing the arginine (R) at amino acid position 21 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Benign
0.16
T;T;T;T;T;T
Eigen
Benign
-0.63
Eigen_PC
Benign
-0.81
FATHMM_MKL
Benign
0.035
N
LIST_S2
Benign
0.73
.;.;T;T;T;T
M_CAP
Benign
0.031
D
MetaRNN
Benign
0.13
T;T;T;T;T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Uncertain
2.0
M;M;.;.;M;.
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.25
T
PROVEAN
Uncertain
-2.4
N;.;.;.;.;.
REVEL
Benign
0.085
Sift
Uncertain
0.0010
D;.;.;.;.;.
Sift4G
Uncertain
0.026
D;.;D;D;.;D
Polyphen
0.99
D;D;.;.;D;.
Vest4
0.15
MutPred
0.33
Gain of catalytic residue at L19 (P = 0.0026);Gain of catalytic residue at L19 (P = 0.0026);Gain of catalytic residue at L19 (P = 0.0026);Gain of catalytic residue at L19 (P = 0.0026);Gain of catalytic residue at L19 (P = 0.0026);Gain of catalytic residue at L19 (P = 0.0026);
MVP
0.78
MPC
0.20
ClinPred
0.19
T
GERP RS
-0.048
Varity_R
0.073
gMVP
0.42

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs754238733; hg19: chr17-38445733; COSMIC: COSV52931573; COSMIC: COSV52931573; API