12-57749282-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000075.4(CDK4):c.719G>A(p.Arg240Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. R240G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000075.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDK4 | NM_000075.4 | c.719G>A | p.Arg240Gln | missense_variant | 7/8 | ENST00000257904.11 | |
TSPAN31 | NM_005981.5 | c.*1992C>T | 3_prime_UTR_variant | 6/6 | ENST00000257910.8 | ||
TSPAN31 | NM_001330168.2 | c.*1992C>T | 3_prime_UTR_variant | 4/4 | |||
TSPAN31 | NM_001330169.2 | c.*1992C>T | 3_prime_UTR_variant | 6/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDK4 | ENST00000257904.11 | c.719G>A | p.Arg240Gln | missense_variant | 7/8 | 1 | NM_000075.4 | P1 | |
TSPAN31 | ENST00000257910.8 | c.*1992C>T | 3_prime_UTR_variant | 6/6 | 1 | NM_005981.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152224Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251364Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135874
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461856Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727228
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152342Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74488
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 13, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26155992) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 03, 2022 | The p.R240Q variant (also known as c.719G>A), located in coding exon 6 of the CDK4 gene, results from a G to A substitution at nucleotide position 719. The arginine at codon 240 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is poorly 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 19, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 240 of the CDK4 protein (p.Arg240Gln). This variant is present in population databases (rs531817742, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with CDK4-related conditions. ClinVar contains an entry for this variant (Variation ID: 236946). 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 with a negative predictive value of 95%. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at