12-57751373-C-T

Variant names:

• chr12-57751373-C-T
• rs2270777
• ENST00000551706.1:n.554G>A

Variant summary

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

The ENST00000551706.1(CDK4):​n.554G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 1,613,034 control chromosomes in the GnomAD database, including 131,121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9608 hom., cov: 31)
  • Exomes 𝑓: 0.40 (121513 hom.)
• Consequence: CDK4 ENST00000551706.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.04
• Publications: 27 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=-0.81).
• BP6: Variant 12-57751373-C-T is Benign according to our data. Variant chr12-57751373-C-T is described in ClinVar as Benign. ClinVar VariationId is 1249096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK4	NM_000075.4	c.219-31G>A		intron_variant	Intron 2 of 7	ENST00000257904.11	NP_000066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK4	ENST00000257904.11	c.219-31G>A		intron_variant	Intron 2 of 7	1	NM_000075.4	ENSP00000257904.5

Frequencies

GnomAD3 genomes AF: 0.333 AC: 50642 AN: 151902 Hom.: 9617 Cov.: 31

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.518

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.350

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.409

GnomAD2 exomes AF: 0.341 AC: 85676 AN: 251084 AF XY: 0.349

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.234

Gnomad ASJ exome AF: 0.515

Gnomad EAS exome AF: 0.158

Gnomad FIN exome AF: 0.356

Gnomad NFE exome AF: 0.435

Gnomad OTH exome AF: 0.403

GnomAD4 exome AF: 0.398 AC: 581727 AN: 1461014 Hom.: 121513 Cov.: 39 AF XY: 0.396 AC XY: 287839 AN XY: 726856

African (AFR) AF: 0.158 AC: 5280 AN: 33472

American (AMR) AF: 0.248 AC: 11094 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.508 AC: 13266 AN: 26136

East Asian (EAS) AF: 0.123 AC: 4899 AN: 39694

South Asian (SAS) AF: 0.245 AC: 21152 AN: 86240

European-Finnish (FIN) AF: 0.367 AC: 19541 AN: 53208

Middle Eastern (MID) AF: 0.501 AC: 2874 AN: 5740

European-Non Finnish (NFE) AF: 0.432 AC: 479885 AN: 1111432

Other (OTH) AF: 0.393 AC: 23736 AN: 60370

GnomAD4 genome AF: 0.333 AC: 50621 AN: 152020 Hom.: 9608 Cov.: 31 AF XY: 0.328 AC XY: 24383 AN XY: 74298

African (AFR) AF: 0.168 AC: 6974 AN: 41492

American (AMR) AF: 0.334 AC: 5100 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 1797 AN: 3466

East Asian (EAS) AF: 0.157 AC: 812 AN: 5182

South Asian (SAS) AF: 0.238 AC: 1145 AN: 4820

European-Finnish (FIN) AF: 0.350 AC: 3684 AN: 10534

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.439 AC: 29807 AN: 67938

Other (OTH) AF: 0.405 AC: 853 AN: 2106

Alfa AF: 0.377 Hom.: 18321

Bravo AF: 0.323

Asia WGS AF: 0.206 AC: 716 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Hereditary cancer-predisposing syndrome Benign:1

Jul 10, 2025

GeneKor MSA

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	-0.81
CADD	Benign	7.0
DANN	Benign	0.82
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs2270777; hg19: chr12-58145156; COSMIC: COSV56985436; COSMIC: COSV56985436;