chr9-21968246-C-A
Variant summary
Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_000077.5(CDKN2A):c.458-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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, intron
Scores
Clinical Significance
Conservation
Publications
- melanoma, cutaneous malignant, susceptibility to, 2Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
- melanoma-pancreatic cancer syndromeInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
- familial atypical multiple mole melanoma syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- melanoma and neural system tumor syndromeInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Likely_benign. The variant received -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDKN2A | NM_000077.5 | c.458-4G>T | splice_region_variant, intron_variant | Intron 2 of 2 | ENST00000304494.10 | NP_000068.1 | ||
CDKN2A | NM_058195.4 | c.*102-4G>T | splice_region_variant, intron_variant | Intron 2 of 2 | ENST00000579755.2 | NP_478102.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.458-4G>T | splice_region_variant, intron_variant | Intron 2 of 2 | 1 | NM_000077.5 | ENSP00000307101.5 | |||
CDKN2A | ENST00000579755.2 | c.*102-4G>T | splice_region_variant, intron_variant | Intron 2 of 2 | 1 | NM_058195.4 | ENSP00000462950.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
The c.458-4G>T intronic variant results from a G to T substitution 4 nucleotides upstream from coding exon 3 in the CDKN2A gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
This variant causes a G to T nucleotide substitution at the -4 position of intron 2 of the CDKN2A (p16INK4A) gene. To our knowledge, RNA functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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. -
Familial melanoma Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at