rs28385701
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_174936.4(PCSK9):c.141C>T(p.Ser47=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00918 in 1,580,712 control chromosomes in the GnomAD database, including 108 homozygotes. 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 0.0083 ( 8 hom., cov: 34)
Exomes 𝑓: 0.0093 ( 100 hom. )
Consequence
PCSK9
NM_174936.4 synonymous
NM_174936.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.90
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 -14 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.49).
BP6
?
Variant 1-55039978-C-T is Benign according to our data. Variant chr1-55039978-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 262902.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=11, Uncertain_significance=2}. Variant chr1-55039978-C-T is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-1.9 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00833 (1270/152386) while in subpopulation SAS AF= 0.0134 (65/4834). AF 95% confidence interval is 0.0108. There are 8 homozygotes in gnomad4. There are 658 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 1270 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCSK9 | NM_174936.4 | c.141C>T | p.Ser47= | synonymous_variant | 1/12 | ENST00000302118.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCSK9 | ENST00000302118.5 | c.141C>T | p.Ser47= | synonymous_variant | 1/12 | 1 | NM_174936.4 | P2 | |
PCSK9 | ENST00000710286.1 | c.498C>T | p.Ser166= | synonymous_variant | 1/12 | A2 | |||
PCSK9 | ENST00000673913.2 | c.141C>T | p.Ser47= | synonymous_variant, NMD_transcript_variant | 1/12 | ||||
PCSK9 | ENST00000673726.1 | c.141C>T | p.Ser47= | synonymous_variant, NMD_transcript_variant | 1/6 |
Frequencies
GnomAD3 genomes ? AF: 0.00835 AC: 1271AN: 152268Hom.: 8 Cov.: 34
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GnomAD3 exomes AF: 0.0100 AC: 1973AN: 196516Hom.: 14 AF XY: 0.0102 AC XY: 1082AN XY: 105660
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GnomAD4 exome AF: 0.00927 AC: 13238AN: 1428326Hom.: 100 Cov.: 31 AF XY: 0.00947 AC XY: 6697AN XY: 707412
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GnomAD4 genome ? AF: 0.00833 AC: 1270AN: 152386Hom.: 8 Cov.: 34 AF XY: 0.00883 AC XY: 658AN XY: 74520
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:15
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Uncertain:2Benign:2
Benign, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | Jan 02, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 02, 2017 | - - |
Uncertain significance, criteria provided, single submitter | research | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | - - |
Uncertain significance, criteria provided, single submitter | research | Iberoamerican FH Network | Mar 01, 2016 | - - |
Hypercholesterolemia, autosomal dominant, 3 Benign:4
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 31, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | PCSK9: BP4, BP7, BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 01, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 21, 2023 | - - |
Hypobetalipoproteinemia Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 08, 2015 | 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. - |
Familial hypercholesterolemia Benign:1
Benign, criteria provided, single submitter | clinical testing | GENinCode PLC | Jul 01, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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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