Genetic Variant CDK4:c.-19-862G>A (chr12-57752598-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000552862.1(CDK4):c.-19-862G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00445 in 152,390 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0044 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0056 ( 0 hom. )

Consequence

CDK4
ENST00000552862.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.479

Publications

2 publications found

Variant links:

COSMIC-nc: COSV106335887

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

CDK4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BS2

High AC in GnomAd4 at 677 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000552862.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CDK4	ENST00000552862.1	TSL:3	c.-19-862G>A	intron	N/A	ENSP00000446763.1	F8W1L8
CDK4	ENST00000551706.1	TSL:1	n.-234G>A	upstream_gene	N/A
CDK4	ENST00000918532.1		c.-438G>A	upstream_gene	N/A	ENSP00000588591.1

Frequencies

GnomAD3 genomes

AF:

0.00444

AC:

676

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000725

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00478

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00701

Gnomad OTH

AF:

0.0105

GnomAD4 exome

AF:

0.00556

AC:

AN:

180

Hom.:

AF XY:

0.00758

AC XY:

AN XY:

132

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00725

AC:

AN:

138

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00445

AC:

677

AN:

152210

Hom.:

Cov.:

AF XY:

0.00451

AC XY:

336

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41526

American (AMR)

AF:

0.00477

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00702

AC:

477

AN:

67996

Other (OTH)

AF:

0.0104

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

101

134

168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00224

Hom.:

Bravo

AF:

0.00467

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

1.8

(source)

DANN

Benign

0.81

PhyloP100

-0.48

PromoterAI

0.021

Neutral

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over