12-57751373-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000075.4(CDK4):c.219-31G>A variant causes a intron 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 NM_000075.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.04

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 1249096.Status of the report is criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
CDK4	NM_000075.4	c.219-31G>A		intron_variant		ENST00000257904.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK4	ENST00000257904.11	c.219-31G>A		intron_variant		1	NM_000075.4	P1

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

GnomAD3 exomes AF: 0.341 AC: 85676 AN: 251084 Hom.: 16487 AF XY: 0.349 AC XY: 47332 AN XY: 135706

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 SAS exome AF: 0.238

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

Gnomad4 AFR exome AF: 0.158

Gnomad4 AMR exome AF: 0.248

Gnomad4 ASJ exome AF: 0.508

Gnomad4 EAS exome AF: 0.123

Gnomad4 SAS exome AF: 0.245

Gnomad4 FIN exome AF: 0.367

Gnomad4 NFE exome AF: 0.432

Gnomad4 OTH exome AF: 0.393

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

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.334

Gnomad4 ASJ AF: 0.518

Gnomad4 EAS AF: 0.157

Gnomad4 SAS AF: 0.238

Gnomad4 FIN AF: 0.350

Gnomad4 NFE AF: 0.439

Gnomad4 OTH AF: 0.405

Alfa AF: 0.329 Hom.: 2147

Bravo AF: 0.323

Asia WGS AF: 0.206 AC: 716 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	7.0
Dann	Benign	0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs2270777; hg19: chr12-58145156; COSMIC: COSV56985436; COSMIC: COSV56985436;