9-21994138-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_058195.4(CDKN2A):c.193+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_058195.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDKN2A | NM_058195.4 | c.193+1G>A | splice_donor_variant, intron_variant | Intron 1 of 2 | ENST00000579755.2 | NP_478102.2 | ||
CDKN2A | NM_001363763.2 | c.-4+683G>A | intron_variant | Intron 1 of 2 | NP_001350692.1 | |||
CDKN2A | XM_047422597.1 | c.-4+409G>A | intron_variant | Intron 1 of 2 | XP_047278553.1 | |||
LOC124902130 | XR_007061436.1 | n.-110G>A | upstream_gene_variant |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not provided Pathogenic:1
This variant is denoted CDKN2A c.193+1G>A or IVS1+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 1B of the of the CDKN2A gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. Of note, the CDKN2A gene encodes the p16 protein and, using an alternate reading frame, the p14-ARF protein as well. As exon 1B is only used by the p14-ARF protein, CDKN2A c.193+1G>A will not affect the p16 protein. This variant has been reported in several individuals with a history of malignant melanoma and shown to segregate with disease in at least two families (Goldstein 2006, Harland 2005, Ghiorzo 2009, Binni 2010, Pedace 2011). We consider this CDKN2A c.193+1G>A to be pathogenic. -
Melanoma-pancreatic cancer syndrome Pathogenic:1
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Familial melanoma Pathogenic:1
This sequence change affects a donor splice site in intron 1 of the CDKN2A (p14ARF) gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with familial cutaneous melanoma (PMID: 21893440, 15856016, 20132244). It has also been observed to segregate with disease in related individuals. Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 15856016). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CDKN2A (p14ARF) are known to be pathogenic (PMID: 11571653, 15856016, 17440112). For these reasons, this variant has been classified as Pathogenic. -
Melanoma, cutaneous malignant, susceptibility to, 2 Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at