rs793888520
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6_Very_StrongBS2_Supporting
The NM_174936.4(PCSK9):βc.449_450delβ(p.Phe150CysfsTer20) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000558 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000013 ( 0 hom., cov: 31)
Exomes π: 0.0000048 ( 0 hom. )
Consequence
PCSK9
NM_174936.4 frameshift
NM_174936.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.40
Genes affected
PCSK9 (HGNC:20001): (proprotein convertase subtilisin/kexin type 9) This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an autocatalytic processing event with its prosegment in the ER and is constitutively secreted as an inactive protease into the extracellular matrix and trans-Golgi network. It is expressed in liver, intestine and kidney tissues and escorts specific receptors for lysosomal degradation. It plays a role in cholesterol and fatty acid metabolism. Mutations in this gene have been associated with autosomal dominant familial hypercholesterolemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP6
?
Variant 1-55046570-CTT-C is Benign according to our data. Variant chr1-55046570-CTT-C is described in ClinVar as [Likely_benign]. Clinvar id is 189307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
?
High AC in GnomAdExome4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCSK9 | NM_174936.4 | c.449_450del | p.Phe150CysfsTer20 | frameshift_variant | 3/12 | ENST00000302118.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCSK9 | ENST00000302118.5 | c.449_450del | p.Phe150CysfsTer20 | frameshift_variant | 3/12 | 1 | NM_174936.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152188Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251484Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135922
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461888Hom.: 0 AF XY: 0.00000688 AC XY: 5AN XY: 727248
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152188Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74346
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ClinVar
Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Benign:1
Likely benign, criteria provided, single submitter | research | Institute for Integrative and Experimental Genomics, University of Luebeck | - | - - |
Familial hypercholesterolemia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 24, 2017 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at