rs778871932
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2
The NM_000077.5(CDKN2A):c.459C>T(p.Asp153Asp) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000077.5 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDKN2A | NM_058195.4 | c.*103C>T | splice_region_variant | 3/3 | ENST00000579755.2 | NP_478102.2 | ||
CDKN2A | NM_000077.5 | c.459C>T | p.Asp153Asp | splice_region_variant, synonymous_variant | 3/3 | ENST00000304494.10 | NP_000068.1 | |
CDKN2A | NM_058195.4 | c.*103C>T | 3_prime_UTR_variant | 3/3 | ENST00000579755.2 | NP_478102.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000579755.2 | c.*103C>T | splice_region_variant | 3/3 | 1 | NM_058195.4 | ENSP00000462950.1 | |||
CDKN2A | ENST00000304494.10 | c.459C>T | p.Asp153Asp | splice_region_variant, synonymous_variant | 3/3 | 1 | NM_000077.5 | ENSP00000307101.5 | ||
CDKN2A | ENST00000579755 | c.*103C>T | 3_prime_UTR_variant | 3/3 | 1 | NM_058195.4 | ENSP00000462950.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152154Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251192Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135808
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461658Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7AN XY: 727142
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74326
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 23, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 31, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 13, 2014 | 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 provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 15, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 15, 2024 | Variant summary: CDKN2A c.459C>T (p.Asp153Asp) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation 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 2e-05 in 251192 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.459C>T in individuals affected with Cutaneous Malignant Melanoma and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 236990). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Familial melanoma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at