rs587778185

chr12-57751081-G-Achr12-57751081-G-Cchr12-57751081-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000075.4(CDK4):c.364C>T(p.Arg122Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. R122H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: CDK4 NM_000075.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5 O:1
• Conservation: PhyloP100: 0.439

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 Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37228715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK4	NM_000075.4	c.364C>T	p.Arg122Cys	missense_variant	4/8	ENST00000257904.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK4	ENST00000257904.11	c.364C>T	p.Arg122Cys	missense_variant	4/8	1	NM_000075.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251482 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461874 Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Melanoma, cutaneous malignant, susceptibility to, 3 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 07, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 12, 2018	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 19, 2018

This variant is denoted CDK4 c.364C>T at the cDNA level, p.Arg122Cys (R122C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDK4 Arg122Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). CDK4 Arg122Cys is located in the protein kinase domain (UniProt). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CDK4 Arg122Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2022

The p.R122C variant (also known as c.364C>T), located in coding exon 3 of the CDK4 gene, results from a C to T substitution at nucleotide position 364. The arginine at codon 122 is replaced by cysteine, an amino acid with highly dissimilar 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

Nov 20, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 122 of the CDK4 protein (p.Arg122Cys). This variant is present in population databases (rs587778185, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CDK4-related conditions. ClinVar contains an entry for this variant (Variation ID: 133874). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.37
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.;T;.;.;T
Eigen	Benign	0.050
Eigen_PC	Benign	-0.037
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.30	T;T;T;T;T;T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.37	T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.3	L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.5	D;D;D;D;D;D
REVEL	Benign	0.21
Sift	Benign	0.065	T;T;T;T;T;T
Sift4G	Benign	0.12	T;T;.;.;T;.
Polyphen		0.99	D;.;.;.;.;.
Vest4		0.20
MutPred		0.51		Loss of catalytic residue at R122 (P = 0.0629);.;.;.;Loss of catalytic residue at R122 (P = 0.0629);Loss of catalytic residue at R122 (P = 0.0629);
MVP		0.73
MPC		0.87
ClinPred		0.65	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.67

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: rs587778185; hg19: chr12-58144864; COSMIC: COSV99225862; COSMIC: COSV99225862;