chr12-57749277-C-A

Position:

• chr12-57749277-C-A

Variant summary

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

The ENST00000257904.11(CDK4):​c.724G>T​(p.Val242Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. V242A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDK4 ENST00000257904.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.94

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK4	NM_000075.4	c.724G>T	p.Val242Leu	missense_variant	7/8	ENST00000257904.11	NP_000066.1
TSPAN31	NM_005981.5	c.*1987C>A		3_prime_UTR_variant	6/6	ENST00000257910.8	NP_005972.1
TSPAN31	NM_001330168.2	c.*1987C>A		3_prime_UTR_variant	4/4		NP_001317097.1
TSPAN31	NM_001330169.2	c.*1987C>A		3_prime_UTR_variant	6/6		NP_001317098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK4	ENST00000257904.11	c.724G>T	p.Val242Leu	missense_variant	7/8	1	NM_000075.4	ENSP00000257904	P1
TSPAN31	ENST00000257910.8	c.*1987C>A		3_prime_UTR_variant	6/6	1	NM_005981.5	ENSP00000257910	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial melanoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 07, 2021

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. 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. This variant has not been reported in the literature in individuals with CDK4-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 242 of the CDK4 protein (p.Val242Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.50	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.21	N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.28
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.24	T;T;.
Polyphen		0.47	P;.;.
Vest4		0.53
MutPred		0.41		Gain of methylation at R246 (P = 0.1971);.;.;
MVP		0.79
MPC		0.62
ClinPred		0.90	D
GERP RS		4.6
Varity_R		0.65
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-58143060;