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rs2495482

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_174936.4(PCSK9):c.207+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.944 in 1,553,126 control chromosomes in the GnomAD database, including 692,792 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.92 ( 64013 hom., cov: 38)
Exomes 𝑓: 0.95 ( 628779 hom. )

Consequence

PCSK9
NM_174936.4 intron

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.224
Variant links:
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 -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
Variant 1-55040059-A-G is Benign according to our data. Variant chr1-55040059-A-G is described in ClinVar as [Benign]. Clinvar id is 262904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55040059-A-G is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.95 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PCSK9NM_174936.4 linkuse as main transcriptc.207+15A>G intron_variant ENST00000302118.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PCSK9ENST00000302118.5 linkuse as main transcriptc.207+15A>G intron_variant 1 NM_174936.4 P2Q8NBP7-1
PCSK9ENST00000710286.1 linkuse as main transcriptc.564+15A>G intron_variant A2
PCSK9ENST00000673726.1 linkuse as main transcriptc.207+15A>G intron_variant, NMD_transcript_variant
PCSK9ENST00000673913.2 linkuse as main transcriptc.207+15A>G intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.915
AC:
139342
AN:
152240
Hom.:
63976
Cov.:
38
show subpopulations
Gnomad AFR
AF:
0.835
Gnomad AMI
AF:
0.952
Gnomad AMR
AF:
0.903
Gnomad ASJ
AF:
0.929
Gnomad EAS
AF:
0.943
Gnomad SAS
AF:
0.973
Gnomad FIN
AF:
0.969
Gnomad MID
AF:
0.920
Gnomad NFE
AF:
0.951
Gnomad OTH
AF:
0.921
GnomAD3 exomes
AF:
0.928
AC:
147203
AN:
158652
Hom.:
68556
AF XY:
0.936
AC XY:
79055
AN XY:
84504
show subpopulations
Gnomad AFR exome
AF:
0.830
Gnomad AMR exome
AF:
0.836
Gnomad ASJ exome
AF:
0.928
Gnomad EAS exome
AF:
0.941
Gnomad SAS exome
AF:
0.970
Gnomad FIN exome
AF:
0.965
Gnomad NFE exome
AF:
0.951
Gnomad OTH exome
AF:
0.942
GnomAD4 exome
AF:
0.947
AC:
1326590
AN:
1400768
Hom.:
628779
Cov.:
65
AF XY:
0.949
AC XY:
655717
AN XY:
691306
show subpopulations
Gnomad4 AFR exome
AF:
0.824
Gnomad4 AMR exome
AF:
0.844
Gnomad4 ASJ exome
AF:
0.929
Gnomad4 EAS exome
AF:
0.957
Gnomad4 SAS exome
AF:
0.970
Gnomad4 FIN exome
AF:
0.965
Gnomad4 NFE exome
AF:
0.952
Gnomad4 OTH exome
AF:
0.941
GnomAD4 genome
AF:
0.915
AC:
139434
AN:
152358
Hom.:
64013
Cov.:
38
AF XY:
0.917
AC XY:
68323
AN XY:
74510
show subpopulations
Gnomad4 AFR
AF:
0.835
Gnomad4 AMR
AF:
0.902
Gnomad4 ASJ
AF:
0.929
Gnomad4 EAS
AF:
0.943
Gnomad4 SAS
AF:
0.973
Gnomad4 FIN
AF:
0.969
Gnomad4 NFE
AF:
0.951
Gnomad4 OTH
AF:
0.921
Alfa
AF:
0.919
Hom.:
13492
Bravo
AF:
0.904
Asia WGS
AF:
0.953
AC:
3315
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jun 07, 2018- -
Benign, criteria provided, single submitterclinical testingGeneDxSep 28, 2016This 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. -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Hypercholesterolemia, autosomal dominant, 3 Benign:4
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 05, 2021- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Hypercholesterolemia, familial, 1 Benign:3
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJun 22, 2017- -
Benign, criteria provided, single submitterresearchCardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo JorgeMar 01, 2016- -
Benign, criteria provided, single submitterresearchIberoamerican FH NetworkMar 01, 2016- -
Hypobetalipoproteinemia Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 29, 2023- -
Familial hypercholesterolemia Benign:1
Benign, no assertion criteria providedclinical testingCohesion PhenomicsFeb 09, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
Cadd
Benign
6.8
Dann
Benign
0.46
RBP_binding_hub_radar
0.67
RBP_regulation_power_radar
1.9

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2495482; hg19: chr1-55505732; API