rs199888003
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS2
The NM_058195.4(CDKN2A):c.361G>A(p.Ala121Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000319 in 1,605,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign 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. A121V) has been classified as Likely benign.
Frequency
Consequence
NM_058195.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKN2A | NM_058195.4 | c.361G>A | p.Ala121Thr | missense_variant | 2/3 | ENST00000579755.2 | |
CDKN2A | NM_000077.5 | c.318G>A | p.Val106= | synonymous_variant | 2/3 | ENST00000304494.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000579755.2 | c.361G>A | p.Ala121Thr | missense_variant | 2/3 | 1 | NM_058195.4 | ||
CDKN2A | ENST00000304494.10 | c.318G>A | p.Val106= | synonymous_variant | 2/3 | 1 | NM_000077.5 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.000250 AC: 38AN: 152226Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000221 AC: 52AN: 235136Hom.: 0 AF XY: 0.000201 AC XY: 26AN XY: 129154
GnomAD4 exome AF: 0.000327 AC: 475AN: 1453468Hom.: 0 Cov.: 31 AF XY: 0.000322 AC XY: 233AN XY: 723350
GnomAD4 genome ? AF: 0.000250 AC: 38AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74378
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:5
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 20, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 30, 2023 | Observed in several individuals with melanoma, pancreatic cancer, or other cancers (PMID: 16234564, 17255954, 17218939, 21150883, 25787093, 26225579, 25479140, 26104880, 25980754, 26681309, 28726808, 34326862); In silico analysis supports a deleterious effect on protein structure/function; Reported using an alternate transcript of the gene; Also known as p.Ala162Thr; This variant is associated with the following publications: (PMID: 25064638, 25980754, 30709382, 30039340, 16234564, 21150883, 26104880, 17218939, 12538475, 25787093, 26225579, 17255954, 28726808, 29415044, 27621404, 26681309, 19690981, 25780468, 27882345, 25479140, 16896043, 29641532, 11687599, 8710906, 16818274, 12532425, 27756164, 37322831, 28765326, 34326862, 27960642) - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2023 | CDKN2A: BP4 - |
not specified Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 29, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 04, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 19, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 10, 2014 | Insufficient or inconclusive evidence - |
Maffucci syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine | - | - - |
Melanoma-pancreatic cancer syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Familial melanoma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at