12-57751585-C-T

Position:

• chr12-57751585-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000075.4(CDK4):​c.133G>A​(p.Gly45Ser) 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. 14/21 in silico tools predict a benign outcome for this variant. 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. G45C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDK4 NM_000075.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.571

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]

ACMG classification

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=0.09560409).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK4	NM_000075.4	c.133G>A	p.Gly45Ser	missense_variant	2/8	ENST00000257904.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK4	ENST00000257904.11	c.133G>A	p.Gly45Ser	missense_variant	2/8	1	NM_000075.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2015

The p.G45S variant (also known as c.133G>A), located in coding exon 1 of the CDK4 gene, results from a G to A substitution at nucleotide position 133. The glycine at codon 45 is replaced by serine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 17000 alleles tested) in our clinical cohort. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.G45S remains unclear. -

Familial melanoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 08, 2022

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, which suggests that this missense change does not adversely affect protein function. 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. ClinVar contains an entry for this variant (Variation ID: 233299). 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 glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 45 of the CDK4 protein (p.Gly45Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T;T;.;T;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.13	T;T;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.096	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	0.86	D;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.9	N;N;N;N;N
REVEL	Benign	0.071
Sift	Benign	0.21	T;D;T;T;T
Sift4G	Uncertain	0.023	D;T;T;.;.
Polyphen		0.0	.;B;.;.;.
Vest4		0.19
MutPred		0.42		Gain of glycosylation at G45 (P = 0.0044);Gain of glycosylation at G45 (P = 0.0044);Gain of glycosylation at G45 (P = 0.0044);Gain of glycosylation at G45 (P = 0.0044);Gain of glycosylation at G45 (P = 0.0044);
MVP		0.82
MPC		0.62
ClinPred		0.37	T
GERP RS		0.78
Varity_R		0.25
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs876660318; hg19: chr12-58145368;