chr12-12718118-G-GC
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004064.5(CDKN1B):c.285dup(p.Lys96GlnfsTer29) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R93R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004064.5 frameshift
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 |
---|---|---|---|---|---|---|---|
CDKN1B | NM_004064.5 | c.285dup | p.Lys96GlnfsTer29 | frameshift_variant | 1/3 | ENST00000228872.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKN1B | ENST00000228872.9 | c.285dup | p.Lys96GlnfsTer29 | frameshift_variant | 1/3 | 1 | NM_004064.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461798Hom.: 0 Cov.: 51 AF XY: 0.00 AC XY: 0AN XY: 727208
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia type 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 29, 2023 | This sequence change creates a premature translational stop signal (p.Lys96Glnfs*29) in the CDKN1B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDKN1B are known to be pathogenic (PMID: 17030811, 24819502). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of multiple endocrine neoplasia type 4 (PMID: 32052251). ClinVar contains an entry for this variant (Variation ID: 536843). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 03, 2021 | The c.285dupC pathogenic mutation, located in coding exon 1 of the CDKN1B gene, results from a duplication of C at nucleotide position 285, causing a translational frameshift with a predicted alternate stop codon (p.K96Qfs*29). This variant has been reported in a patient with primary hyperthyroidism, who also had prostate cancer and Neurofibromatosis type 1 (Brock P et al. Fam Cancer, 2020 04;19:189-192). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at