chr12-57751036-C-T
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_000075.4(CDK4):c.409G>A(p.Val137Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,614,146 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. V137L) 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 -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDK4 | NM_000075.4 | c.409G>A | p.Val137Ile | missense_variant | 4/8 | ENST00000257904.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDK4 | ENST00000257904.11 | c.409G>A | p.Val137Ile | missense_variant | 4/8 | 1 | NM_000075.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251450Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135904
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461886Hom.: 0 Cov.: 33 AF XY: 0.0000234 AC XY: 17AN XY: 727244
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152260Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74458
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 30, 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; Observed in individuals with Lynch syndrome-related cancers and/or polyps (Yurgelun et al., 2015); This variant is associated with the following publications: (PMID: 36243179, 25980754) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 24, 2019 | - - |
CDK4-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 04, 2023 | The CDK4 c.409G>A variant is predicted to result in the amino acid substitution p.Val137Ile. This variant has been reported in an individual undergoing Lynch syndrome genetic testing (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754). This variant is reported in 5 of ~283,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/12-58144819-C-T). This variant is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/216268/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 04, 2023 | The p.V137I variant (also known as c.409G>A), located in coding exon 3 of the CDK4 gene, results from a G to A substitution at nucleotide position 409. The valine at codon 137 is replaced by isoleucine, an amino acid with highly similar 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 | Jan 24, 2024 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 137 of the CDK4 protein (p.Val137Ile). This variant is present in population databases (rs150281463, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of CDK4-related conditions (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 216268). 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