rs144481587
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000077.5(CDKN2A):c.-25C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00231 in 1,542,830 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.012 ( 29 hom., cov: 32)
Exomes 𝑓: 0.0013 ( 34 hom. )
Consequence
CDKN2A
NM_000077.5 5_prime_UTR
NM_000077.5 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.60
Genes affected
CDKN2A (HGNC:1787): (cyclin dependent kinase inhibitor 2A) This gene generates several transcript variants which differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, the E3 ubiquitin-protein ligase MDM2, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene. [provided by RefSeq, Sep 2012]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.73).
BP6
?
Variant 9-21974852-G-A is Benign according to our data. Variant chr9-21974852-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 127522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0116 (1768/152204) while in subpopulation AFR AF= 0.0396 (1646/41528). AF 95% confidence interval is 0.038. There are 29 homozygotes in gnomad4. There are 841 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 1768 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKN2A | NM_000077.5 | c.-25C>T | 5_prime_UTR_variant | 1/3 | ENST00000304494.10 | ||
CDKN2A | NM_058195.4 | c.194-3644C>T | intron_variant | ENST00000579755.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.-25C>T | 5_prime_UTR_variant | 1/3 | 1 | NM_000077.5 | P2 | ||
CDKN2A | ENST00000579755.2 | c.194-3644C>T | intron_variant | 1 | NM_058195.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0115 AC: 1746AN: 152086Hom.: 27 Cov.: 32
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GnomAD3 exomes AF: 0.00313 AC: 470AN: 150394Hom.: 8 AF XY: 0.00257 AC XY: 213AN XY: 82720
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GnomAD4 exome AF: 0.00129 AC: 1791AN: 1390626Hom.: 34 Cov.: 31 AF XY: 0.00112 AC XY: 769AN XY: 687472
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GnomAD4 genome ? AF: 0.0116 AC: 1768AN: 152204Hom.: 29 Cov.: 32 AF XY: 0.0113 AC XY: 841AN XY: 74418
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:6
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 20, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 28, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Variant identifed in melanoma patients and in vitro functional assay show mild impact on expression (Bisio_2010_20093296). Not related to our patient phenotype and and high allele frequency. - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 22, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 16, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 23, 2019 | - - |
Melanoma-pancreatic cancer syndrome Benign:4
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 20, 2023 | This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. - |
Benign, criteria provided, single submitter | clinical testing | Counsyl | May 25, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | CDKN2A: BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 16, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 16, 2021 | This variant is associated with the following publications: (PMID: 25980754, 14735200, 11078762, 25356972, 26775776, 18983535, 16397522, 21801156, 25318351, 18335566, 28830827, 20093296, 26581427) - |
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 19, 2014 | General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 30, 2020 | - - |
Familial melanoma Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at