12-57751272-C-G

Variant summary

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

The NM_000075.4(CDK4):c.289G>C(p.Asp97His) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. D97E) 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: 2.60

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK4	NM_000075.4	c.289G>C	p.Asp97His	missense_variant	3/8	ENST00000257904.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK4	ENST00000257904.11	c.289G>C	p.Asp97His	missense_variant	3/8	1	NM_000075.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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 24, 2022

The p.D97H variant (also known as c.289G>C), located in coding exon 2 of the CDK4 gene, results from a G to C substitution at nucleotide position 289. The aspartic acid at codon 97 is replaced by histidine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial melanoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 07, 2016

This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in the germline of individuals with a CDK4-related disease. This sequence change replaces aspartic acid with histidine at codon 97 of the CDK4 protein (p.Asp97His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D;.;T;.;.;T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.2	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.4	D;D;D;D;D;D;D
REVEL	Benign	0.15
Sift	Benign	0.13	T;D;T;T;T;T;T
Sift4G	Uncertain	0.056	T;T;.;.;T;.;.
Polyphen		0.51	P;.;.;.;.;.;.
Vest4		0.26
MutPred		0.56		Loss of phosphorylation at T102 (P = 0.1599);.;.;.;Loss of phosphorylation at T102 (P = 0.1599);Loss of phosphorylation at T102 (P = 0.1599);Loss of phosphorylation at T102 (P = 0.1599);
MVP		0.73
MPC		1.2
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.76
gMVP		0.81

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

LitVar

Other links and lift over

dbSNP: rs1060501932; hg19: chr12-58145055; COSMIC: COSV105857074; COSMIC: COSV105857074;