rs761577371
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000075.4(CDK4):āc.863G>Cā(p.Arg288Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R288G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000075.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDK4 | NM_000075.4 | c.863G>C | p.Arg288Pro | missense_variant | 8/8 | ENST00000257904.11 | |
TSPAN31 | NM_005981.5 | c.*1284C>G | 3_prime_UTR_variant | 6/6 | ENST00000257910.8 | ||
MIR6759 | NR_106817.1 | downstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDK4 | ENST00000257904.11 | c.863G>C | p.Arg288Pro | missense_variant | 8/8 | 1 | NM_000075.4 | P1 | |
TSPAN31 | ENST00000257910.8 | c.*1284C>G | 3_prime_UTR_variant | 6/6 | 1 | NM_005981.5 | P1 | ||
MIR6759 | ENST00000638110.1 | downstream_gene_variant |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461664Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 727136
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 05, 2018 | The p.R288P variant (also known as c.863G>C), located in coding exon 7 of the CDK4 gene, results from a G to C substitution at nucleotide position 863. The arginine at codon 288 is replaced by proline, an amino acid with 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 | Dec 10, 2020 | 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. ClinVar contains an entry for this variant (Variation ID: 822622). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 288 of the CDK4 protein (p.Arg288Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at