rs749588877
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_000077.5(CDKN2A):βc.407delβ(p.Gly136AlafsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,564 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ). Synonymous variant affecting the same amino acid position (i.e. G136G) has been classified as Likely benign.
Frequency
Consequence
NM_000077.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKN2A | NM_000077.5 | c.407del | p.Gly136AlafsTer10 | frameshift_variant | 2/3 | ENST00000304494.10 | |
CDKN2A | NM_058195.4 | c.*51del | 3_prime_UTR_variant | 2/3 | ENST00000579755.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.407del | p.Gly136AlafsTer10 | frameshift_variant | 2/3 | 1 | NM_000077.5 | P2 | |
CDKN2A | ENST00000579755.2 | c.*51del | 3_prime_UTR_variant | 2/3 | 1 | NM_058195.4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459564Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726162
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 17, 2020 | This variant deletes 1 nucleotide in exon 2 of the CDKN2A (p16INK4A) gene, creating a frameshift and premature translation stop signal. This variant is not expected to trigger nonsense-mediated decay, and it is predicted to truncate the C-terminus of the ankyrin repeat domain. Truncation variants that delete the ankyrin repeat domain and are reported as disease-causing in ClinVar all impact conserved motifs in the ankyrin repeat (ClinVar variation ID: 216035, 406710, 463500, 463503, 573002). However, this variant truncates the protein after the last conserved motif (PMID: 8880901, 12519945). To our knowledge, functional studies have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDKN2A function is a known mechanism of disease (clinicalgenome.org). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 24, 2018 | The c.407delG variant, located in coding exon 2 of the CDKN2A gene, results from a deletion of one nucleotide at nucleotide position 407, causing a translational frameshift with a predicted alternate stop codon (p.G136Afs*10). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of CDKN2A, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 21 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time. 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 | Mar 09, 2020 | This variant has not been reported in the literature in individuals with CDKN2A (p16INK4a)-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the CDKN2A (p16INK4a) gene (p.Gly136Alafs*10). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 21 amino acids of the CDKN2A (p16INK4a) protein. 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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at