rs28362268
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_174936.4(PCSK9):c.1431C>T(p.Cys477=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000906 in 1,612,056 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0045 ( 4 hom., cov: 32)
Exomes 𝑓: 0.00053 ( 3 hom. )
Consequence
PCSK9
NM_174936.4 synonymous
NM_174936.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.163
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 -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.77).
BP6
Variant 1-55058575-C-T is Benign according to our data. Variant chr1-55058575-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 413318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55058575-C-T is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-0.163 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00451 (686/152252) while in subpopulation AFR AF= 0.0151 (626/41548). AF 95% confidence interval is 0.0141. There are 4 homozygotes in gnomad4. There are 324 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 686 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCSK9 | NM_174936.4 | c.1431C>T | p.Cys477= | synonymous_variant | 9/12 | ENST00000302118.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCSK9 | ENST00000302118.5 | c.1431C>T | p.Cys477= | synonymous_variant | 9/12 | 1 | NM_174936.4 | P2 |
Frequencies
GnomAD3 genomes AF: 0.00448 AC: 682AN: 152134Hom.: 4 Cov.: 32
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GnomAD3 exomes AF: 0.00124 AC: 311AN: 251138Hom.: 2 AF XY: 0.000913 AC XY: 124AN XY: 135838
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GnomAD4 exome AF: 0.000530 AC: 774AN: 1459804Hom.: 3 Cov.: 108 AF XY: 0.000453 AC XY: 329AN XY: 726202
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GnomAD4 genome AF: 0.00451 AC: 686AN: 152252Hom.: 4 Cov.: 32 AF XY: 0.00435 AC XY: 324AN XY: 74436
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 19, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 12, 2016 | Variant summary: The PCSK9 c.1431C>T (p.Cys477Cys) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 192/120408 control chromosomes (3 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.017144 (176/10266). This frequency is about 183 times the estimated maximal expected allele frequency of a pathogenic PCSK9 variant (0.0000938), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. Taken together, this variant is classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 08, 2019 | - - |
Hypercholesterolemia, autosomal dominant, 3 Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 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. - |
Familial hypercholesterolemia Benign:2
Benign, criteria provided, single submitter | clinical testing | GENinCode PLC | Jan 12, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 24, 2017 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 18, 2018 | - - |
Hypobetalipoproteinemia Benign:1
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. - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 29, 2017 | This alteration is classified as 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
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Name
Calibrated prediction
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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