rs1064793970
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP3
The NM_000077.5(CDKN2A):c.11_16del(p.Ala4_Ala5del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A4A) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
CDKN2A
NM_000077.5 inframe_deletion
NM_000077.5 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.859
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 Uncertain_significance. Variant got 3 ACMG points.
PM1
In a chain Cyclin-dependent kinase inhibitor 2A (size 155) in uniprot entity CDN2A_HUMAN there are 119 pathogenic changes around while only 33 benign (78%) in NM_000077.5
PM2
Very rare variant in population databases, with high coverage;
BP3
Nonframeshift variant in repetitive region in NM_000077.5
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKN2A | NM_000077.5 | c.11_16del | p.Ala4_Ala5del | inframe_deletion | 1/3 | ENST00000304494.10 | |
CDKN2A | NM_058195.4 | c.194-3609_194-3604del | intron_variant | ENST00000579755.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.11_16del | p.Ala4_Ala5del | inframe_deletion | 1/3 | 1 | NM_000077.5 | P2 | |
CDKN2A | ENST00000579755.2 | c.194-3609_194-3604del | intron_variant | 1 | NM_058195.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 29, 2015 | This deletion of 6 nucleotides in CDKN2A is denoted c.11_16delCGGCGG at the cDNA level and p.Ala4_Ala5del (A4_A5del) at the protein level, and results in the deletion of two Alanine residues of the p16 protein. The normal sequence, with the bases that are deleted in braces, is CCGG[CGGCGG]GGAG. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDKN2A Ala4_Ala5del occurs in a region that is not conserved and is not located in a known functional domain (UniProt). Since in frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider CDKN2A Ala4_Ala5del to be a variant of uncertain significance. - |
Familial melanoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 26, 2020 | 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. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. This variant has not been reported in the literature in individuals with CDKN2A (p16INK4a)-related disease. ClinVar contains an entry for this variant (Variation ID: 419581). This variant is not present in population databases (ExAC no frequency). This variant, c.11_16delCGGCGG, results in the deletion of 2 amino acids of the CDKN2A (p16INK4a) protein (p.Ala4_Ala5del), but otherwise preserves the integrity of the reading frame. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at