9-21971159-C-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_000077.5(CDKN2A):c.200G>A(p.Gly67Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000188 in 1,594,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G67R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000077.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKN2A | NM_000077.5 | c.200G>A | p.Gly67Asp | missense_variant | 2/3 | ENST00000304494.10 | |
CDKN2A | NM_058195.4 | c.243G>A | p.Arg81= | synonymous_variant | 2/3 | ENST00000579755.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.200G>A | p.Gly67Asp | missense_variant | 2/3 | 1 | NM_000077.5 | P2 | |
CDKN2A | ENST00000579755.2 | c.243G>A | p.Arg81= | synonymous_variant | 2/3 | 1 | NM_058195.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152176Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.93e-7 AC: 1AN: 1442672Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1AN XY: 717780
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74330
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 14, 2023 | The p.G67D variant (also known as c.200G>A), located in coding exon 2 of the CDKN2A gene, results from a G to A substitution at nucleotide position 200. The glycine at codon 67 is replaced by aspartic acid, an amino acid with similar properties. Other amino acid substitutions at this same codon (arginine and serine) have been identified in multiple familial melanoma and pancreatic cancer kindreds but did not segregate completely with disease in these families (Kannengiesser C et al. Hum. Mutat. 2009 Apr;30(4):564-74; Holland EA et al. Genes Chromosomes Cancer, 1999 Aug;25:339-48; Newton Bishop JA et al. Br. J. Cancer 1999 Apr;80(1-2):295-300; Bishop DT et al. J. Natl. Cancer Inst., 2002 Jun;94:894-903; Goldstein AM. J. Med. Genet. 2007 Feb;44(2):99-106; Miller PJ et al. Hum. Mutat. 2011 Aug;32(8):900-11; Ghiorzo P. J. Med. Genet. 2012 Mar;49(3):164-70). In functional studies, both of these close-match alterations also showed an intermediate defect in CDK4 and CDK6 binding as well as and intermediate defect in cell proliferation (Kannengiesser C et al. Hum. Mutat. 2009 Apr;30(4):564-74; Rizos H et al. J. Biol. Chem. 2001 Nov;276(44):41424-34; McKenzie HA et al. Hum. Mutat. 2010 Jun; 31(6):692-701). While these various functional studies don't agree on the effect that the close-matches have on cell cycle inhibition, they do agree that sub-cellular localization appears abnormal for these variants (Miller PJ et al. Hum. Mutat. 2011 Aug;32(8):900-11; Rizos H et al. J. Biol. Chem. 2001 Nov;276(44):41424-34; McKenzie HA et al. Hum. Mutat. 2010 Jun; 31(6):692-701). Internal structural analysis predicts that CDKN2A p.G67D will be similarly destabilizing to the local structure as the close-match alterations (Russo AA. Nature. 1998 Sep;395(6699):237-43; Kannengiesser C et al. Hum. Mutat. 2009 Apr;30(4):564-74; Rizos H et al. J. Biol. Chem. 2001 Nov;276(44):41424-34; Ambry internal data), however, since direct supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 05, 2023 | The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). This missense variant replaces glycine with aspartic acid at codon 67 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CDKN2A-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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. - |
Familial melanoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 67 of the CDKN2A (p16INK4a) protein (p.Gly67Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. ClinVar contains an entry for this variant (Variation ID: 216273). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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