rs371488778
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP3
The NM_174936.4(PCSK9):c.42_43insATGCTG(p.Pro14_Leu15insMetLeu) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 152,070 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L15L) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Consequence
PCSK9
NM_174936.4 conservative_inframe_insertion
NM_174936.4 conservative_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.246
Publications
8 publications found
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]
PCSK9 Gene-Disease associations (from GenCC):
- hypercholesterolemia, autosomal dominant, 3Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- homozygous familial hypercholesterolemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP3
Nonframeshift variant in repetitive region in NM_174936.4
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_174936.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PCSK9 | MANE Select | c.42_43insATGCTG | p.Pro14_Leu15insMetLeu | conservative_inframe_insertion | Exon 1 of 12 | NP_777596.2 | |||
| PCSK9 | c.42_43insATGCTG | p.Pro14_Leu15insMetLeu | conservative_inframe_insertion | Exon 1 of 13 | NP_001394169.1 | A0AAQ5BGX4 | |||
| PCSK9 | c.42_43insATGCTG | p.Pro14_Leu15insMetLeu | conservative_inframe_insertion | Exon 1 of 12 | NP_001394170.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PCSK9 | TSL:1 MANE Select | c.42_43insATGCTG | p.Pro14_Leu15insMetLeu | conservative_inframe_insertion | Exon 1 of 12 | ENSP00000303208.5 | Q8NBP7-1 | ||
| PCSK9 | c.399_400insATGCTG | p.Pro133_Leu134insMetLeu | conservative_inframe_insertion | Exon 1 of 12 | ENSP00000518176.1 | A0AA34QVH0 | |||
| PCSK9 | c.42_43insATGCTG | p.Pro14_Leu15insMetLeu | conservative_inframe_insertion | Exon 1 of 13 | ENSP00000519088.1 | A0AAQ5BGX4 |
Frequencies
GnomAD3 genomes 0.0000132 AC: 2AN: 152070Hom.: 0 Cov.: 31 show subpopulations
GnomAD3 genomes
AF:
AC:
2
AN:
152070
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
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Gnomad MID
AF:
Gnomad NFE
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Gnomad OTH
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GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome 0.0000132 AC: 2AN: 152070Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74294 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome
AF:
AC:
2
AN:
152070
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
74294
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
2
AN:
41404
American (AMR)
AF:
AC:
0
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3468
East Asian (EAS)
AF:
AC:
0
AN:
5174
South Asian (SAS)
AF:
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
AC:
0
AN:
10602
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
0
AN:
67996
Other (OTH)
AF:
AC:
0
AN:
2088
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
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0.95
Allele balance
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions
View on ClinVar Significance:Uncertain significance
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
-
1
-
Hypercholesterolemia, autosomal dominant, 3 (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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