chr9-21971037-C-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000077.5(CDKN2A):c.322G>A(p.Asp108Asn) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D108Y) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000077.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKN2A | NM_000077.5 | c.322G>A | p.Asp108Asn | missense_variant | 2/3 | ENST00000304494.10 | |
CDKN2A | NM_058195.4 | c.365G>A | p.Arg122Gln | missense_variant | 2/3 | ENST00000579755.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.322G>A | p.Asp108Asn | missense_variant | 2/3 | 1 | NM_000077.5 | P2 | |
CDKN2A | ENST00000579755.2 | c.365G>A | p.Arg122Gln | missense_variant | 2/3 | 1 | NM_058195.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000138 AC: 2AN: 1453704Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 723436
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 23, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 14, 2022 | The p.D108N variant (also known as c.322G>A), located in coding exon 2 of the CDKN2A gene, results from a G to A substitution at nucleotide position 322. The aspartic acid at codon 108 is replaced by asparagine, an amino acid with highly similar properties. This variant has been detected in multiple familial melanoma cohorts; however, in one family two of the four affected members did not carry the variant, and in another family one member also carried another pathogenic variant CDKN2A p.M53T (Flores JF et al. Oncogene. 1997 Dec;15:2999-3005; Aitken J et al. J. Natl. Cancer Inst. 1999 Mar;91:446-52; Bishop DT et al. J. Natl. Cancer Inst. 2002 Jun;94:894-903; Begg CB et al. J. Natl. Cancer Inst. 2005 Oct;97:1507-15; Goldstein AM et al. Cancer Res. 2006 Oct;66:9818-28; Berwick M et al. Cancer Epidemiol. Biomarkers Prev. 2006 Aug;15:1520-5; Orlow I et al. J. Invest. Dermatol. 2007 May;127:1234-43; Goldstein AM et al. J. Med. Genet. 2007 Feb;44:99-106; Huot TJ et al. Mol. Cell. Biol. 2002 Dec;22:8135-43; Miller PJ et al. Hum. Mutat. 2011 Aug;32:900-11). Two functional studies agree that this variant has an intermediate defect in binding to CDK4, however, they disagree about whether there is a defect in CDK6 binding (Huot TJ et al. Mol. Cell. Biol. 2002 Dec;22:8135-43; Hallett ST et al. Cell Rep. 2017 Oct;21:1386-1398). One of these studies also reports that this variant causes a significant reduction in protein stability, however, this concept was not recapitulated in other functional studies with tagged-exogenous material (Hallett ST et al. Cell Rep. 2017 Oct;21:1386-1398; Huot TJ et al. Mol. Cell. Biol. 2002 Dec;22:8135-43, respectively). Lastly, another functional study showed that cell cycle arrest was not affected by this variant (Miller PJ et al. Hum. Mutat. 2011 Aug;32:900-11). CDKN2A p.D108N sits at the interface with other binding partners, including CDK4/6 and it is anticipated to result in a decrease in protein-protein interactions (Russo AA et al. Nature. 1998 Sep;395:237-43; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
not provided Uncertain:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 06, 2015 | This variant is denoted CDKN2A c.322G>A at the cDNA level, p.Asp108Asn (D108N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). This variant has been reported in several high-risk melanoma families (Flores 1997, Bishop 2002, Begg 2005, Goldstein 2006, Goldstein 2007, Aoude 2015). Additionally, Huot et al. (2002) identified CDKN2A Asp108Asn in an individual found to harbor a second CDKN2A variant (suspected biallelic). While an in vitro assay completed by Huot et al. (2002) showed that this variant results in a reduced ability to bind CDK4 and CDK6 compared to wild-type, another in vitro assay completed by Miller et al. (2011) showed the this variants retains cell cycle arrest function comparable to wild-type. CDKN2A Asp108Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. CDKN2A Asp108Asn occurs at a position that is conserved across species and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether CDKN2A Asp108Asn is pathogenic or benign. We consider it to be a variant of uncertain significance. - |
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpretted as Uncertain significance and reported on 06-22-2019 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Familial melanoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 02, 2023 | The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 108 of the CDKN2A (p16INK4a) protein (p.Asp108Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with melanoma (PMID: 9416844, 16234564, 21462282; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.365G>A (p.Arg122Gln) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 216275). 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. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 12417717, 21462282, 29091774). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at