12-57751036-C-T

Position:

chr12-57751036-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000075.4(CDK4):c.409G>A(p.Val137Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,614,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. V137L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

CDK4
NM_000075.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.423

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13349646).

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK4	NM_000075.4 linkuse as main transcript	c.409G>A	p.Val137Ile	missense_variant	4/8	ENST00000257904.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK4	ENST00000257904.11 linkuse as main transcript	c.409G>A	p.Val137Ile	missense_variant	4/8	1	NM_000075.4	P1	P11802-1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251450

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with Lynch syndrome-related cancers and/or polyps (Yurgelun et al., 2015); This variant is associated with the following publications: (PMID: 36243179, 25980754) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 24, 2019	- -

CDK4-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 04, 2023

The CDK4 c.409G>A variant is predicted to result in the amino acid substitution p.Val137Ile. This variant has been reported in an individual undergoing Lynch syndrome genetic testing (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754). This variant is reported in 5 of ~283,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/12-58144819-C-T). This variant is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/216268/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2023

The p.V137I variant (also known as c.409G>A), located in coding exon 3 of the CDK4 gene, results from a G to A substitution at nucleotide position 409. The valine at codon 137 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial melanoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 137 of the CDK4 protein (p.Val137Ile). This variant is present in population databases (rs150281463, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of CDK4-related conditions (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 216268). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CDK4 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.29

T;.;T;.;.;T

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.79

T;T;T;T;T;T

M_CAP

Benign

0.0061

MetaRNN

Benign

0.13

T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.21

N;.;.;.;.;.

MutationTaster

Benign

0.84

D;D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.41

N;N;N;N;N;N

REVEL

Benign

0.051

Sift

Benign

0.45

T;T;T;T;T;T

Sift4G

Benign

0.50

T;T;.;.;T;.

Polyphen

0.019

B;.;.;.;.;.

Vest4

0.080

MutPred

0.46

Loss of catalytic residue at V137 (P = 0.0381);.;.;.;Loss of catalytic residue at V137 (P = 0.0381);Loss of catalytic residue at V137 (P = 0.0381);

MVP

0.56

MPC

0.51

ClinPred

0.057

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

gMVP

0.11

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over