12-57751549-C-A

Variant names:

• chr12-57751549-C-A
• rs1555201369
• NM_000075.4:c.169G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000075.4(CDK4):​c.169G>T​(p.Val57Leu) variant causes a missense change. 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. V57M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDK4 NM_000075.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.97
• 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: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000075.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK4	NM_000075.4	MANE Select	c.169G>T	p.Val57Leu	missense	Exon 2 of 8	NP_000066.1	P11802-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK4	ENST00000257904.11	TSL:1 MANE Select	c.169G>T	p.Val57Leu	missense	Exon 2 of 8	ENSP00000257904.5	P11802-1
	CDK4	ENST00000551706.1	TSL:1	n.378G>T		non_coding_transcript_exon	Exon 2 of 3
	CDK4	ENST00000547281.5	TSL:3	c.-54G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	ENSP00000447274.1	F8VZZ0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial melanoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.80	N
PhyloP100		6.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.018	D
Polyphen		0.65	P
Vest4		0.75
MutPred		0.78		Loss of helix (P = 0.0304)
MVP		0.92
MPC		0.75
ClinPred		0.96	D
GERP RS		5.2
PromoterAI		0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		0.81
Mutation Taster		=124/176	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.60		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.60		Position offset: 6

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

Other links and lift over

dbSNP: rs1555201369; hg19: chr12-58145332;