12-57751333-G-T

Variant names:

• chr12-57751333-G-T
• rs772531745
• NM_000075.4:c.228C>A

Variant summary

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

The NM_000075.4(CDK4):​c.228C>A​(p.Asp76Glu) 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D76D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDK4 NM_000075.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.64
• Publications: 0 publications found

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

ACMG classification

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
CDK4	NM_000075.4	c.228C>A	p.Asp76Glu	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.228C>A	p.Asp76Glu	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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D76E variant (also known as c.228C>A), located in coding exon 2 of the CDK4 gene, results from a C to A substitution at nucleotide position 228. The aspartic acid at codon 76 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is conserved. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T;.;T;.;.;T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.74	T;T;T;T;T;T;T;T
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.1	.;L;.;.;.;.;.;.
PhyloP100		-1.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D;D;D
REVEL	Uncertain	0.39
Sift	Benign	0.080	T;T;T;T;T;T;T;T
Sift4G	Pathogenic	0.0	D;T;T;.;.;T;.;.
Polyphen		0.99	.;D;.;.;.;.;.;.
Vest4		0.69
MutPred		0.79		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;.;.;Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.80
MPC		1.3
ClinPred		0.91	D
GERP RS		-6.2
Varity_R		0.80
gMVP		0.77
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs772531745; hg19: chr12-58145116;