rs606231175
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM4BP6BS2
The NM_000077.5(CDKN2A):c.9_32delGGCGGCGGGGAGCAGCATGGAGCC(p.Ala4_Pro11del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000952 in 1,606,464 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00024 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000080 ( 0 hom. )
Consequence
CDKN2A
NM_000077.5 disruptive_inframe_deletion
NM_000077.5 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.62
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 Likely_benign. Variant got -1 ACMG points.
PM1
In a chain Cyclin-dependent kinase inhibitor 2A (size 155) in uniprot entity CDN2A_HUMAN there are 42 pathogenic changes around while only 12 benign (78%) in NM_000077.5
PM4
Nonframeshift variant in NON repetitive region in NM_000077.5.
BP6
Variant 9-21974795-AGGCTCCATGCTGCTCCCCGCCGCC-A is Benign according to our data. Variant chr9-21974795-AGGCTCCATGCTGCTCCCCGCCGCC-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 216277.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=9}.
BS2
High AC in GnomAd4 at 37 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDKN2A | NM_000077.5 | c.9_32delGGCGGCGGGGAGCAGCATGGAGCC | p.Ala4_Pro11del | disruptive_inframe_deletion | 1/3 | ENST00000304494.10 | NP_000068.1 | |
CDKN2A | NM_058195.4 | c.194-3611_194-3588delGGCGGCGGGGAGCAGCATGGAGCC | intron_variant | ENST00000579755.2 | NP_478102.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.9_32delGGCGGCGGGGAGCAGCATGGAGCC | p.Ala4_Pro11del | disruptive_inframe_deletion | 1/3 | 1 | NM_000077.5 | ENSP00000307101.5 | ||
CDKN2A | ENST00000579755.2 | c.194-3611_194-3588delGGCGGCGGGGAGCAGCATGGAGCC | intron_variant | 1 | NM_058195.4 | ENSP00000462950.1 |
Frequencies
GnomAD3 genomes AF: 0.000243 AC: 37AN: 151972Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000145 AC: 34AN: 233942Hom.: 0 AF XY: 0.000132 AC XY: 17AN XY: 129094
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GnomAD4 exome AF: 0.0000798 AC: 116AN: 1454492Hom.: 0 AF XY: 0.0000760 AC XY: 55AN XY: 723908
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GnomAD4 genome AF: 0.000243 AC: 37AN: 151972Hom.: 1 Cov.: 32 AF XY: 0.000377 AC XY: 28AN XY: 74232
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Melanoma-pancreatic cancer syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 20, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 13, 2016 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 17, 2024 | In-frame deletion of 8 amino acid(s) in a non-repeat region; Observed in families with multiple cases of melanoma, demonstrating incomplete segregation with disease in at least one family, and in individuals with breast cancer (PMID: 10070944, 12072543, 17047042, 16905682, 20876876, 25780468, 25803691, 26976419, 35264596); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17047042, 25780468, 10070944, 12072543, 16905682, 19759551, 25803691, 26976419, 20876876, 27196769, 21325014, 28830827, 35264596, 28765326, 27756164, 27960642, 18519632, 16818274, 11159196, 9166859, 7718873, 15146471, 37059229, 37833309, 36243179) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 03, 2017 | - - |
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 26, 2024 | Variant summary: CDKN2A c.9_32del24 (p.Ala4_Pro11del) results in an in-frame deletion that is predicted to remove 8 amino acids from the encoded protein. The variant allele was found at a frequency of 9.5e-05 in 1608632 control chromosomes, predominantly at a frequency of 0.0009 within the Latino subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDKN2A causing Cutaneous Malignant Melanoma phenotype (0.0003), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.9_32del24 has been reported in the literature in individuals affected with Cutaneous Malignant Melanoma (Aitken_1999, Bishop_2002, Goldstein_2006, Goldstein_2007, Harland_2014, Wadt_2015, Cust_2011). However, these reports do not provide unequivocal conclusions about an association of the variant with Cutaneous Malignant Melanoma. The following publications have been ascertained in the context of this evaluation (PMID: 10070944, 12072543, 27756164, 27960642, 28765326, 21325014, 17047042, 15146471, 16905682, 25780468, 19759551, 9166859, 16818274, 18519632, 11159196, 7718873, 26976419, 25803691, 36243179, 35264596). ClinVar contains an entry for this variant (Variation ID: 216277). 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 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 21, 2023 | This variant results in a deletion of eight amino acids from the N-terminus of the CDKN2A (p16INK4A) protein. The residues deleted by this variant (p.Ala4_Pro11) are only present in human and two other non-human primate species. The mutant allele is a reference in other mammalian species (https://genome.ucsc.edu/). A functional study has shown that the mutant protein resulting from this variant retains normal protein function (PMID: 8668202). This variant has been reported in over ten individuals affected by melanoma (PMID: 10070944, 12072543, 16905682, 17047042, 19759551, 20876876, 21325014, 25780468, 25803691) and breast cancer (PMID: 26976419). This variant has also been identified in 36/265240 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and is particularly common in the Latino population (0.0512%, 18/35104 alleles). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 11, 2022 | 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. - |
Melanoma and neural system tumor syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 13, 2024 | - - |
Familial melanoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 21, 2024 | This variant, c.9_32del, results in the deletion of 8 amino acid(s) of the CDKN2A (p16INK4a) protein (p.Ala4_Pro11del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs751570838, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with breast cancer and melanoma (PMID: 12072543, 16905682, 17047042, 19759551, 20876876, 25780468, 25803691, 26976419). ClinVar contains an entry for this variant (Variation ID: 216277). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at