rs864622636
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000077.5(CDKN2A):c.148C>T(p.Gln50Ter) variant causes a stop gained, splice region change. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Q50Q) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000077.5 stop_gained, splice_region
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKN2A | NM_000077.5 | c.148C>T | p.Gln50Ter | stop_gained, splice_region_variant | 1/3 | ENST00000304494.10 | |
CDKN2A | NM_058195.4 | c.194-3472C>T | intron_variant | ENST00000579755.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.148C>T | p.Gln50Ter | stop_gained, splice_region_variant | 1/3 | 1 | NM_000077.5 | P2 | |
CDKN2A | ENST00000579755.2 | c.194-3472C>T | intron_variant | 1 | NM_058195.4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Melanoma and neural system tumor syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 08, 2023 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 23, 2016 | This variant is denoted CDKN2A c.148C>T at the cDNA level and p.Gln50Ter (Q50X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Consistent with predictions, Parry et al (1996) demonstrated via Cdk binding assays that this variant results in a truncated protein that is unable to bind to CDK2, CDK4, or CDK6. This variant has been reported in an individual with pancreatic cancer and her father with melanoma, and was also observed in at least one individual with multiple primary melanomas (Bartsch 2002, Pastorino 2008). Based on currently available evidence, we consider this variant pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 26, 2022 | The p.Q50* pathogenic mutation (also known as c.148C>T), located in coding exon 1 of the CDKN2A gene, results from a C to T substitution at nucleotide position 148. This changes the amino acid from a glutamine to a stop codon within coding exon 1. This pathogenic variant has been identified in numerous individuals from melanoma and pancreatic cancer cohorts (Bartsch DK et al. Ann. Surg. 2002 Dec;236:730-7; Pastorino L et al. Pigment Cell Melanoma Res. 2008 Dec;21:700-9; Zhen DB et al. Genet. Med. 2015 Jul;17:569-77). The p.Q50* pathogenic mutation has also shown an inability to bind to Cdk4 and Cdk6 when assessed in vitro (Parry D et al. Mol. Cell. Biol. 1996 Jul;16:3844-52). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Familial melanoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 15, 2023 | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 220711). This variant is also known as 50Q>X. This premature translational stop signal has been observed in individual(s) with pancreatic cancer and melanoma (PMID: 12454511, 18983535, 25356972, 25877891). This sequence change creates a premature translational stop signal (p.Gln50*) in the CDKN2A (p16INK4a) gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDKN2A (p16INK4a) are known to be pathogenic (PMID: 15146471, 16905682). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at