12-57751316-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000075.4(CDK4):​c.245G>C​(p.Arg82Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R82G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CDK4
NM_000075.4 missense

Scores

1
11
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.95

Publications

12 publications found
Variant links:
Genes affected
CDK4 (HGNC:1773): (cyclin dependent kinase 4) The protein encoded by this gene is a member of the Ser/Thr protein kinase family. This protein is highly similar to the gene products of S. cerevisiae cdc28 and S. pombe cdc2. It is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression. The activity of this kinase is restricted to the G1-S phase, which is controlled by the regulatory subunits D-type cyclins and CDK inhibitor p16(INK4a). This kinase was shown to be responsible for the phosphorylation of retinoblastoma gene product (Rb). Mutations in this gene as well as in its related proteins including D-type cyclins, p16(INK4a) and Rb were all found to be associated with tumorigenesis of a variety of cancers. Multiple polyadenylation sites of this gene have been reported. [provided by RefSeq, Jul 2008]
CDK4 Gene-Disease associations (from GenCC):
  • melanoma, cutaneous malignant, susceptibility to, 3
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
  • malignant pancreatic neoplasm
    Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDK4NM_000075.4 linkc.245G>C p.Arg82Pro missense_variant Exon 3 of 8 ENST00000257904.11 NP_000066.1 P11802-1A0A024RBB6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CDK4ENST00000257904.11 linkc.245G>C p.Arg82Pro missense_variant Exon 3 of 8 1 NM_000075.4 ENSP00000257904.5 P11802-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Familial melanoma Uncertain:1
Jul 19, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CDK4 protein function. ClinVar contains an entry for this variant (Variation ID: 939801). This variant has not been reported in the literature in individuals affected with CDK4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 82 of the CDK4 protein (p.Arg82Pro). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.54
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
-0.040
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Benign
0.29
T;D;.;T;.;.;T;.
Eigen
Benign
0.085
Eigen_PC
Benign
0.090
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.96
D;D;D;D;D;D;D;D
M_CAP
Benign
0.073
D
MetaRNN
Uncertain
0.45
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.47
T
MutationAssessor
Benign
0.29
.;N;.;.;.;.;.;.
PhyloP100
4.0
PrimateAI
Uncertain
0.54
T
PROVEAN
Uncertain
-4.3
D;D;D;D;D;D;D;D
REVEL
Uncertain
0.34
Sift
Uncertain
0.0060
D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;.;.;D;.;.
Polyphen
0.99
.;D;.;.;.;.;.;.
Vest4
0.60
MutPred
0.31
Loss of solvent accessibility (P = 0.0364);Loss of solvent accessibility (P = 0.0364);.;.;.;Loss of solvent accessibility (P = 0.0364);Loss of solvent accessibility (P = 0.0364);Loss of solvent accessibility (P = 0.0364);
MVP
0.88
MPC
0.91
ClinPred
0.88
D
GERP RS
3.2
Varity_R
0.88
gMVP
0.88
Mutation Taster
=39/61
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs3211612; hg19: chr12-58145099; API