1-55039879-ACTG-A
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2
The NM_174936.4(PCSK9):c.63_65del(p.Leu23del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000267 in 1,553,698 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L15L) has been classified as Likely benign.
Frequency
Consequence
NM_174936.4 inframe_deletion
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 |
---|---|---|---|---|---|---|---|
PCSK9 | NM_174936.4 | c.63_65del | p.Leu23del | inframe_deletion | 1/12 | ENST00000302118.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCSK9 | ENST00000302118.5 | c.63_65del | p.Leu23del | inframe_deletion | 1/12 | 1 | NM_174936.4 | P2 | |
PCSK9 | ENST00000710286.1 | c.420_422del | p.Leu142del | inframe_deletion | 1/12 | A2 | |||
PCSK9 | ENST00000673726.1 | c.63_65del | p.Leu23del | inframe_deletion, NMD_transcript_variant | 1/6 | ||||
PCSK9 | ENST00000673913.2 | c.63_65del | p.Leu23del | inframe_deletion, NMD_transcript_variant | 1/12 |
Frequencies
GnomAD3 genomes AF: 0.000631 AC: 96AN: 152066Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000695 AC: 112AN: 161082Hom.: 0 AF XY: 0.000696 AC XY: 60AN XY: 86248
GnomAD4 exome AF: 0.000228 AC: 319AN: 1401516Hom.: 1 AF XY: 0.000227 AC XY: 157AN XY: 692260
GnomAD4 genome AF: 0.000631 AC: 96AN: 152182Hom.: 0 Cov.: 31 AF XY: 0.000753 AC XY: 56AN XY: 74418
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Uncertain:2Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | Jan 02, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 07, 2017 | - - |
Uncertain significance, criteria provided, single submitter | research | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | - - |
Benign, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Uncertain significance, criteria provided, single submitter | research | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | Mar 01, 2016 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 11, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 13, 2019 | Variant summary: PCSK9 c.63_65delGCT (p.Leu23del) results in an in-frame deletion that is predicted to remove a Leu amino acid from the encoded protein. The variant allele was found at a frequency of 0.0007 in 161082 control chromosomes. The observed variant frequency is approximately 35-folds over the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Early Onset Coronary Artery Disease phenotype (2e-05), strongly suggesting that the variant is benign. Five ClinVar submissions (evaluation after 2014) cites the variant three times as likely benign and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. - |
Hypercholesterolemia, autosomal dominant, 3 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
PCSK9-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 04, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 07, 2020 | This variant is associated with the following publications: (PMID: 33303402, 29572815) - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 12, 2018 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at