rs11547328

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000075.4(CDK4):c.70C>T(p.Arg24Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R24H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CDK4
NM_000075.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 7.90

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 Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-57751647-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

PP5

Variant 12-57751648-G-A is Pathogenic according to our data. Variant chr12-57751648-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-57751648-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK4	NM_000075.4 link	c.70C>T	p.Arg24Cys	missense_variant	2/8	ENST00000257904.11	NP_000066.1	P11802-1A0A024RBB6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK4	ENST00000257904.11 link	c.70C>T	p.Arg24Cys	missense_variant	2/8	1	NM_000075.4	ENSP00000257904.5		P11802-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251466

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 27, 2023	The p.R24C pathogenic mutation (also known as c.70C>T), located in coding exon 1 of the CDK4 gene, results from a C to T substitution at nucleotide position 70. The arginine at codon 24 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in the literature to segregate with melanoma in six different families (Zuo L et al. Nat. Genet., 1996 Jan;12:97-9; Puntervoll HE et al. J. Med. Genet., 2013 Apr;50:264-70). Additionally, this variant has been shown to disrupt p16INK4a binding and inhibition of CDK4, which results in an increase in CDK4 kinase activity (Wölfel T et al. Science, 1995 Sep;269:1281-4). Mouse in vivo studies demonstrated that mice with this variant showed significantly increased susceptibility to the development of CDK4 related tumors (Rane SG et al. Mol. Cell. Biol., 2002 Jan;22:644-56). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 30, 2020	This missense variant replaces arginine with cysteine at codon 24 of the CDK4 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental functional studies have shown that this variant impairs interaction with CDKN2A (p16-INK4a) preventing inhibition by p16-INK4a and allowing for unregulated CDK4 kinase activity, cell cycle progression and cellular transformation (PMID: 11756559, 7652577, 9228064). This variant has been reported in individuals affected with melanoma (PMID: 8528263, 22804906 23384855) and has been shown to segregate with disease (PMID: 23384855, 8528263). This variant has been identified in 1/251466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Familial melanoma

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 15, 2017	Variant summary: The CDK4 c.70C>T (p.Arg24Cys) variant involves the alteration of a conserved nucleotide and is located in protein kinase domain of the protein (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/121378 control chromosomes from ExAC at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic CDK4 variant (0.00002). This variant has been reported in six unrelated cutaneous malignant melanoma families including evidence of cosegregation with disease (Zuo_1996, Ghiorzo_2012, Puntervoll_2013). In vivo mice-model study shows the recapitulation of melanoma phenotype (Rane_2002). The codon p.Arg24 is a mutational hot-spot in which another mutation p.Arg24His is known to be pathogenic. Multiple clinical diagnostic laboratories in ClinVar have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 06, 2022	This variant is present in population databases (rs11547328, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 24 of the CDK4 protein (p.Arg24Cys). This missense change has been observed in individual(s) with melanoma (PMID: 8528263, 23384855). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16928). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CDK4 function (PMID: 7652577, 11756559). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Melanoma, cutaneous malignant, susceptibility to, 3

Pathogenic:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 26, 2016	- -
risk factor, no assertion criteria provided	literature only	OMIM	Jan 01, 1996	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 26, 2016

This pathogenic variant is denoted CDK4 c.70C>T at the cDNA level, p.Arg24Cys (R24C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has been reported to segregate with melanoma in several melanoma families (Zuo 1996, Puntervoll 2013). Functional studies have shown that this variant disrupts binding with CDKN2A, resulting in resistance to CDKN2A inhibition and increased CDK4 kinase activity (Wolfel 1995, Rane 2002). CDK4 Arg24Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDK4 Arg24Cys occurs at a position that is conserved across species and is located in the protein kinase domain (UniProt). In silico analyses are inconsistent regarding the effect this pathogenic variant may have on protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;D;.;T;.

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Uncertain

0.086

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.5

.;M;.;.;.

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-6.7

D;D;D;D;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.016

D;D;D;D;D

Sift4G

Uncertain

0.045

D;T;D;.;.

Polyphen

0.74

.;P;.;.;.

Vest4

0.94

MutPred

0.90

Loss of disorder (P = 0.0238);Loss of disorder (P = 0.0238);Loss of disorder (P = 0.0238);Loss of disorder (P = 0.0238);Loss of disorder (P = 0.0238);

MVP

0.91

MPC

1.2

ClinPred

0.98

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.80

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.20

Position offset: -14

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