12-57751581-C-T

Position:

• chr12-57751581-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.137G>A​(p.Gly46Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDK4 NM_000075.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.83

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=0.10825923).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK4	NM_000075.4	c.137G>A	p.Gly46Glu	missense_variant	2/8	ENST00000257904.11	NP_000066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK4	ENST00000257904.11	c.137G>A	p.Gly46Glu	missense_variant	2/8	1	NM_000075.4	ENSP00000257904	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727228

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Apr 05, 2024

The p.G46E variant (also known as c.137G>A), located in coding exon 1 of the CDK4 gene, results from a G to A substitution at nucleotide position 137. The glycine at codon 46 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Familial melanoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2020

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CDK4-related disease. ClinVar contains an entry for this variant (Variation ID: 236941). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 46 of the CDK4 protein (p.Gly46Glu). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Benign	0.89
DEOGEN2	Benign	0.18	T;T;.;T;.
Eigen	Benign	-0.067
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.83	T;T;T;T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.52	.;N;.;.;.
MutationTaster	Benign	0.72	D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	4.5	N;N;N;N;N
REVEL	Benign	0.068
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Uncertain	0.033	D;T;T;.;.
Polyphen		0.0080	.;B;.;.;.
Vest4		0.35
MutPred		0.41		Gain of solvent accessibility (P = 0.012);Gain of solvent accessibility (P = 0.012);Gain of solvent accessibility (P = 0.012);Gain of solvent accessibility (P = 0.012);Gain of solvent accessibility (P = 0.012);
MVP		0.44
MPC		0.80
ClinPred		0.53	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.29
gMVP		0.13

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: rs878853622; hg19: chr12-58145364;