chr9-21970954-C-T
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_000077.5(CDKN2A):c.405G>A(p.Gly135=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,611,984 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G135G) has been classified as Likely benign.
Frequency
Consequence
NM_000077.5 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -21 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKN2A | NM_000077.5 | c.405G>A | p.Gly135= | synonymous_variant | 2/3 | ENST00000304494.10 | |
CDKN2A | NM_058195.4 | c.*49G>A | 3_prime_UTR_variant | 2/3 | ENST00000579755.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.405G>A | p.Gly135= | synonymous_variant | 2/3 | 1 | NM_000077.5 | P2 | |
CDKN2A | ENST00000579755.2 | c.*49G>A | 3_prime_UTR_variant | 2/3 | 1 | NM_058195.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152244Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000813 AC: 20AN: 245898Hom.: 0 AF XY: 0.0000448 AC XY: 6AN XY: 133852
GnomAD4 exome AF: 0.000200 AC: 292AN: 1459740Hom.: 2 Cov.: 31 AF XY: 0.000186 AC XY: 135AN XY: 726260
GnomAD4 genome ? AF: 0.0000920 AC: 14AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74384
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 21, 2016 | - - |
Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Feb 20, 2018 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 02, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 18, 2016 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 28, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 29, 2019 | Variant summary: CDKN2A c.405G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-05 in 272432 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.0011 in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDKN2A causing Cutaneous Malignant Melanoma phenotype (0.0003), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Moreover, the variant was also reported in Japanese healthy controls with a frequency of 0.0108 that is approximately 36-fold of the estimated maximal expected allele frequency for a pathogenic variant in CDKN2A causing Cutaneous Malignant Melanoma phenotype (0.0003), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian/Japanese origin (HGVD). The variant, c.405G>A, has been reported in the literature in individuals from the Japanese population, who were affected with different types of cancer, however without evidence supporting causality (Igaki_1995, Ohnishi_1995, Morita_1998, Takahira_2004). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (1x) / likely benign (4x). Based on the evidence outlined above, the variant was classified as benign. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 17, 2019 | This variant is associated with the following publications: (PMID: 7478613, 1648379, 9132280, 7632931, 2877398, 7614482) - |
Familial melanoma Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at