12-57751647-C-T

Position:

• chr12-57751647-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000075.4(CDK4):​c.71G>A​(p.Arg24His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R24C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDK4 NM_000075.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 6.00

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 (HGNC:):

ACMG classification

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 chr12-57751648-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant 12-57751647-C-T is Pathogenic according to our data. Variant chr12-57751647-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-57751647-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK4	NM_000075.4	c.71G>A	p.Arg24His	missense_variant	2/8	ENST00000257904.11	NP_000066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK4	ENST00000257904.11	c.71G>A	p.Arg24His	missense_variant	2/8	1	NM_000075.4	ENSP00000257904.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2024

The p.R24H pathogenic mutation (also known as c.71G>A), located in coding exon 1 of the CDK4 gene, results from a G to A substitution at nucleotide position 71. The arginine at codon 24 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in multiple unrelated individuals with personal and/or family history consistent with familial melanoma, and has been shown to segregate with disease in multiple large Norwegian, French, and Australian kindreds (Soufir N et al. Hum. Mol. Genet., 1998 Feb;7:209-16; Molven A et al. Genes Chromosomes Cancer, 2005 Sep;44:10-8; Nikolaou V et al. Br. J. Dermatol., 2011 Dec;165:1219-22; Puntervoll HE et al. J. Med. Genet., 2013 Apr;50:264-70; Veinalde R et al. Melanoma Res., 2013 Jun;23:221-6; Karagianni F et al. Acta Derm. Venereol., 2018 Oct;98:862-866). Further, functional analyses of an alteration at the same codon, p.R24C, have shown reduced p16INK4A inhibition of CDK4 kinase activity and cell cycle progression (Bartkova J et al. Cancer Res., 1996 Dec;56:5475-83; Coleman KG et al. J. Biol. Chem., 1997 Jul;272:18869-74). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial melanoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2022

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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 16929). This missense change has been observed in individual(s) with cutaneous melanoma (PMID: 9425228, 15880589, 23384855, 23546221). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 24 of the CDK4 protein (p.Arg24His). This variant disrupts the p.Arg24 amino acid residue in CDK4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7652577, 8528263, 11756559, 23384855). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Melanoma, cutaneous malignant, susceptibility to, 3 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Sep 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T;D;.;T;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.7	.;L;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.1	D;D;D;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;.;.
Polyphen		0.32	.;B;.;.;.
Vest4		0.92
MutPred		0.89		Loss of MoRF binding (P = 0.0602);Loss of MoRF binding (P = 0.0602);Loss of MoRF binding (P = 0.0602);Loss of MoRF binding (P = 0.0602);Loss of MoRF binding (P = 0.0602);
MVP		0.86
MPC		1.7
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.86
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs104894340; hg19: chr12-58145430; COSMIC: COSV56984378; COSMIC: COSV56984378;