12-57751081-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_000075.4(CDK4):c.364C>G(p.Arg122Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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
Consequence
NM_000075.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDK4 | NM_000075.4 | c.364C>G | p.Arg122Gly | missense_variant | 4/8 | ENST00000257904.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDK4 | ENST00000257904.11 | c.364C>G | p.Arg122Gly | missense_variant | 4/8 | 1 | NM_000075.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152088Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461874Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727238
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152088Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74280
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 09, 2022 | The p.R122G variant (also known as c.364C>G), located in coding exon 3 of the CDK4 gene, results from a C to G substitution at nucleotide position 364. The arginine at codon 122 is replaced by glycine, 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 | Oct 03, 2022 | 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. ClinVar contains an entry for this variant (Variation ID: 824029). This variant has not been reported in the literature in individuals affected with CDK4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 122 of the CDK4 protein (p.Arg122Gly). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at