12-57751251-G-C

Variant names:

• chr12-57751251-G-C
• NM_000075.4:c.310C>G

Variant summary

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

The NM_000075.4(CDK4):​c.310C>G​(p.Leu104Val) 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 (★★).

• 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: 0.541

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 rank	MANE	Protein	UniProt
CDK4	NM_000075.4	c.310C>G	p.Leu104Val	missense_variant	Exon 3 of 8	ENST00000257904.11	NP_000066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK4	ENST00000257904.11	c.310C>G	p.Leu104Val	missense_variant	Exon 3 of 8	1	NM_000075.4	ENSP00000257904.5

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

Apr 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L104V variant (also known as c.310C>G), located in coding exon 2 of the CDK4 gene, results from a C to G substitution at nucleotide position 310. The leucine at codon 104 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Familial melanoma Uncertain:1

Aug 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 104 of the CDK4 protein (p.Leu104Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDK4-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;T;.;.;T;.
Eigen	Benign	0.079
Eigen_PC	Benign	0.077
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T;T;T;T;T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	2.0	M;.;.;.;.;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0030	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;.;.;D;.;.
Polyphen		0.66	P;.;.;.;.;.;.
Vest4		0.34
MutPred		0.62		Loss of stability (P = 0.1365);.;.;.;Loss of stability (P = 0.1365);Loss of stability (P = 0.1365);Loss of stability (P = 0.1365);
MVP		0.84
MPC		0.94
ClinPred		0.90	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.89
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-58145034;