rs786201539
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2
The NM_000077.5(CDKN2A):āc.425A>Gā(p.His142Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,612,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H142D) has been classified as Uncertain significance.
Frequency
Consequence
NM_000077.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKN2A | NM_000077.5 | c.425A>G | p.His142Arg | missense_variant | 2/3 | ENST00000304494.10 | |
CDKN2A | NM_058195.4 | c.*69A>G | 3_prime_UTR_variant | 2/3 | ENST00000579755.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.425A>G | p.His142Arg | missense_variant | 2/3 | 1 | NM_000077.5 | P2 | |
CDKN2A | ENST00000579755.2 | c.*69A>G | 3_prime_UTR_variant | 2/3 | 1 | NM_058195.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152238Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 246972Hom.: 0 AF XY: 0.00000746 AC XY: 1AN XY: 134132
GnomAD4 exome AF: 0.0000158 AC: 23AN: 1460164Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 726462
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152238Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74384
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 23, 2022 | This missense variant replaces histidine with arginine at codon 142 of the CDKN2A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant impairs protein interaction with the binding partners, leukemogenic potential, and CDK4/6 inhibitory function of the CDKN2A protein (PMID: 20522552, 28218424, 34369425). Most of the variant effect on protein function was reported to be mild. This variant has been reported in four individuals affected with melanoma (PMID: 18983535, 19158841, 21462282) and in an individual affected with acute lymphoblastic leukemia (PMID: 26104880). One of the individuals affected with melanoma was reported to carry a pathogenic variant in the same gene (PMID: 18983535). This variant has been identified in 3/246972 chromosomes 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | True Health Diagnostics | Apr 06, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 07, 2023 | The p.H142R variant (also known as c.425A>G), located in coding exon 2 of the CDKN2A gene, results from an A to G substitution at nucleotide position 425. The histidine at codon 142 is replaced by arginine, an amino acid with highly similar properties. This variant was previously detected as a germline alteration in a patient with multiple melanomas, who also harbored a pathogenic CDKN2A mutation and in an unrelated sporadic single melanoma patient (Pastorino et al. Pigment Cell Melanoma Res. 2008 Dec;21:700-9). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 18, 2022 | The CDKN2A c.425A>G; p.His142Arg variant (rs759922342) is reported in the literature in individuals affected with melanoma or acute lymphoblastic leukemia (Daniotti 2009, Miller 2011, Pastorino 2008, Xu 2015). However, at least one affected individual carrying this variant also carried a known pathogenic variant in CDKN2A (Pastorino 2008). The p.His142Arg variant is found on three chromosomes (3/246972 alleles) in the Genome Aggregation Database. The histidine at codon 142 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.441). However, functional studies of the variant protein suggest reduced tumor suppressor activity (Li 2022) and reduced interaction with binding partner proteins (Sun 2010). Due to conflicting information, the clinical significance of the p.His142Arg variant is uncertain at this time. References: Daniotti et al. Cutaneous melanoma in childhood and adolescence shows frequent loss of INK4A and gain of KIT. J Invest Dermatol. 2009; 129(7): 1759-1768. PMID: 19158841. Li C et al. The functional role of inherited CDKN2A variants in childhood acute lymphoblastic leukemia. Pharmacogenet Genomics. 2022 Feb 1;32(2):43-50. PMID: 34369425. Miller et al. Classifying variants of CDKN2A using computational and laboratory studies. Hum Mutat. 2011; 32(8): 900-911. PMID: 21462282. Pastorino et al. CDKN2A mutations and MC1R variants in Italian patients with single or multiple primary melanoma. Pigment Cell Melanoma Res. 2008; 21(6): 700-709. PMID: 18983535. Sun et al. GRIM-19 and p16(INK4a) synergistically regulate cell cycle progression and E2F1-responsive gene expression. J Biol Chem. 2010; 285(36): 27545-27552. PMID: 20522552. Xu et al. Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children. Nat Commun. 2015; 6:7553. PMID: 26104880. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 20, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with melanoma; however, one of these individuals also harbored a pathogenic CDKN2A variant, as well as in individual(s) with leukemia (Pastorino et al., 2008; Daniotti et al., 2009; Xu et al., 2015; Vergani et al., 2021; Li et al., 2022); This variant is associated with the following publications: (PMID: 26104880, 21462282, 8834170, 18983535, 9132280, 19158841, 21619050, 20522552, 34573422, 34426522, 34369425) - |
Familial melanoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 142 of the CDKN2A (p16INK4a) protein (p.His142Arg). This variant is present in population databases (rs759922342, gnomAD 0.002%). This missense change has been observed in individual(s) with acute lymphoblastic leukemia and/or melanoma (PMID: 18983535, 19158841, 21462282, 26104880). ClinVar contains an entry for this variant (Variation ID: 184564). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 20522552, 34369425). 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