rs1060501261
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_000077.5(CDKN2A):c.388C>T(p.Leu130=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,611,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
CDKN2A
NM_000077.5 synonymous
NM_000077.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 3.04
Genes affected
CDKN2A (HGNC:1787): (cyclin dependent kinase inhibitor 2A) This gene generates several transcript variants which differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, the E3 ubiquitin-protein ligase MDM2, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene. [provided by RefSeq, Sep 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 9-21970971-G-A is Benign according to our data. Variant chr9-21970971-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 491575.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| CDKN2A | NM_000077.5 | c.388C>T | p.Leu130= | synonymous_variant | 2/3 | ENST00000304494.10 | |
| CDKN2A | NM_058195.4 | c.*32C>T | 3_prime_UTR_variant | 2/3 | ENST00000579755.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CDKN2A | ENST00000304494.10 | c.388C>T | p.Leu130= | synonymous_variant | 2/3 | 1 | NM_000077.5 | P2 | |
| CDKN2A | ENST00000579755.2 | c.*32C>T | 3_prime_UTR_variant | 2/3 | 1 | NM_058195.4 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152238Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000408 AC: 1AN: 245266Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133514
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GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459060Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 725948
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GnomAD4 genome 0.00000657 AC: 1AN: 152238Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74382
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 14, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 26, 2023 | The c.388C>T variant (also known as p.L130L), located in coding exon 2 of the CDKN2A gene, results from a C to T substitution at nucleotide position 388. This nucleotide substitution does not change the leucine at codon 130. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive; and direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Familial melanoma Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Invitae | May 22, 2022 | - - |
Computational scores
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BayesDel_noAF
Benign
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Benign
DANN
Benign
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at