chr12-57749238-G-T

Variant names:

• chr12-57749238-G-T
• rs587778188
• NM_000075.4:c.763C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000075.4(CDK4):​c.763C>A​(p.Arg255Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDK4 NM_000075.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.63

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]

TSPAN31 (HGNC:10539): (tetraspanin 31) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is thought to be involved in growth-related cellular processes. This gene is associated with tumorigenesis and osteosarcoma. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24487376).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK4	NM_000075.4	c.763C>A	p.Arg255Ser	missense_variant	Exon 7 of 8	ENST00000257904.11	NP_000066.1
TSPAN31	NM_005981.5	c.*1948G>T		3_prime_UTR_variant	Exon 6 of 6	ENST00000257910.8	NP_005972.1
TSPAN31	NM_001330169.2	c.*1948G>T		3_prime_UTR_variant	Exon 6 of 6		NP_001317098.1
TSPAN31	NM_001330168.2	c.*1948G>T		3_prime_UTR_variant	Exon 4 of 4		NP_001317097.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK4	ENST00000257904.11	c.763C>A	p.Arg255Ser	missense_variant	Exon 7 of 8	1	NM_000075.4	ENSP00000257904.5
TSPAN31	ENST00000257910.8	c.*1948G>T		3_prime_UTR_variant	Exon 6 of 6	1	NM_005981.5	ENSP00000257910.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Jul 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R255S variant (also known as c.763C>A), located in coding exon 6 of the CDK4 gene, results from a C to A substitution at nucleotide position 763. The arginine at codon 255 is replaced by serine, an amino acid with dissimilar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). 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. Based on the available evidence, the clinical significance of this variant remains unclear. -

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.40	T;.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.2	L;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.082
Sift	Benign	0.10	T;T;D
Sift4G	Benign	0.31	T;T;.
Polyphen		0.0030	B;.;.
Vest4		0.23
MutPred		0.41		Gain of phosphorylation at R255 (P = 0.007);.;.;
MVP		0.76
MPC		0.70
ClinPred		0.81	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.51
gMVP		0.68

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

Other links and lift over

dbSNP: rs587778188; hg19: chr12-58143021;