rs587778188
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_000075.4(CDK4):c.763C>T(p.Arg255Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,614,022 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R255H) has been classified as Likely benign.
Frequency
Consequence
NM_000075.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDK4 | NM_000075.4 | c.763C>T | p.Arg255Cys | missense_variant | 7/8 | ENST00000257904.11 | |
TSPAN31 | NM_005981.5 | c.*1948G>A | 3_prime_UTR_variant | 6/6 | ENST00000257910.8 | ||
TSPAN31 | NM_001330168.2 | c.*1948G>A | 3_prime_UTR_variant | 4/4 | |||
TSPAN31 | NM_001330169.2 | c.*1948G>A | 3_prime_UTR_variant | 6/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDK4 | ENST00000257904.11 | c.763C>T | p.Arg255Cys | missense_variant | 7/8 | 1 | NM_000075.4 | P1 | |
TSPAN31 | ENST00000257910.8 | c.*1948G>A | 3_prime_UTR_variant | 6/6 | 1 | NM_005981.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000519 AC: 13AN: 250598Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135768
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461714Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15AN XY: 727166
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152308Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74472
ClinVar
Submissions by phenotype
not specified Uncertain:2Benign:1Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 26, 2024 | Variant summary: CDK4 c.763C>T (p.Arg255Cys) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 325764 control chromosomes, predominantly at a frequency of 0.00065 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 33-fold of the estimated maximal expected allele frequency for a pathogenic variant in CDK4 causing Cutaneous Malignant Melanoma phenotype (2e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.763C>T has been reported in the literature in individuals affected with Gastric Cancer (e.g. Choi_2021) and suspected hereditary cancer predisposition (e.g. Tsaousis_2019) without evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34285288, 36243179, 31159747). ClinVar contains an entry for this variant (Variation ID: 133877). Based on the evidence outlined above, the variant was classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 31, 2016 | - - |
Melanoma, cutaneous malignant, susceptibility to, 3 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 02, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
Familial melanoma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at