12-57750882-C-T

Variant names:

• chr12-57750882-C-T
• rs2069502
• ENST00000551706.1:n.929G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000075.4(CDK4):​c.522+41G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 1,611,988 control chromosomes in the GnomAD database, including 95,898 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6783 hom., cov: 32)
  • Exomes 𝑓: 0.34 (89115 hom.)
• Consequence: CDK4 NM_000075.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.571
• Publications: 66 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 12-57750882-C-T is Benign according to our data. Variant chr12-57750882-C-T is described in ClinVar as [Benign]. Clinvar id is 1292556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK4	NM_000075.4	c.522+41G>A		intron_variant	Intron 4 of 7	ENST00000257904.11	NP_000066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK4	ENST00000257904.11	c.522+41G>A		intron_variant	Intron 4 of 7	1	NM_000075.4	ENSP00000257904.5

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40423 AN: 152044 Hom.: 6780 Cov.: 32

Gnomad AFR AF: 0.0823

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.652

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.238

GnomAD2 exomes AF: 0.355 AC: 89210 AN: 251364 AF XY: 0.364

Gnomad AFR exome AF: 0.0762

Gnomad AMR exome AF: 0.345

Gnomad ASJ exome AF: 0.278

Gnomad EAS exome AF: 0.637

Gnomad FIN exome AF: 0.365

Gnomad NFE exome AF: 0.321

Gnomad OTH exome AF: 0.308

GnomAD4 exome AF: 0.337 AC: 492646 AN: 1459826 Hom.: 89115 Cov.: 31 AF XY: 0.342 AC XY: 248628 AN XY: 726354

African (AFR) AF: 0.0710 AC: 2373 AN: 33446

American (AMR) AF: 0.334 AC: 14915 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 7548 AN: 26126

East Asian (EAS) AF: 0.702 AC: 27855 AN: 39694

South Asian (SAS) AF: 0.488 AC: 42100 AN: 86204

European-Finnish (FIN) AF: 0.357 AC: 19088 AN: 53420

Middle Eastern (MID) AF: 0.195 AC: 1123 AN: 5764

European-Non Finnish (NFE) AF: 0.323 AC: 358195 AN: 1110114

Other (OTH) AF: 0.322 AC: 19449 AN: 60336

GnomAD4 genome AF: 0.266 AC: 40429 AN: 152162 Hom.: 6783 Cov.: 32 AF XY: 0.274 AC XY: 20381 AN XY: 74384

African (AFR) AF: 0.0821 AC: 3409 AN: 41538

American (AMR) AF: 0.256 AC: 3913 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1005 AN: 3472

East Asian (EAS) AF: 0.652 AC: 3373 AN: 5172

South Asian (SAS) AF: 0.494 AC: 2380 AN: 4814

European-Finnish (FIN) AF: 0.378 AC: 3997 AN: 10578

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.316 AC: 21463 AN: 67978

Other (OTH) AF: 0.236 AC: 499 AN: 2112

Alfa AF: 0.300 Hom.: 25452

Bravo AF: 0.247

Asia WGS AF: 0.516 AC: 1792 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Benign	0.74
PhyloP100		0.57
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2069502; hg19: chr12-58144665; COSMIC: COSV56983640;