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rs11591147

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_174936.4(PCSK9):c.137G>A(p.Arg46His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R46L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

PCSK9
NM_174936.4 missense

Scores

2
17

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.775
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 Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.12675646).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PCSK9NM_174936.4 linkuse as main transcriptc.137G>A p.Arg46His missense_variant 1/12 ENST00000302118.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PCSK9ENST00000302118.5 linkuse as main transcriptc.137G>A p.Arg46His missense_variant 1/121 NM_174936.4 P2Q8NBP7-1
PCSK9ENST00000710286.1 linkuse as main transcriptc.494G>A p.Arg165His missense_variant 1/12 A2
PCSK9ENST00000673913.2 linkuse as main transcriptc.137G>A p.Arg46His missense_variant, NMD_transcript_variant 1/12
PCSK9ENST00000673726.1 linkuse as main transcriptc.137G>A p.Arg46His missense_variant, NMD_transcript_variant 1/6

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1428200
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
707344
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.087
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.47
Cadd
Benign
7.0
Dann
Uncertain
1.0
DEOGEN2
Benign
0.096
T
Eigen
Benign
-0.76
Eigen_PC
Benign
-0.86
FATHMM_MKL
Benign
0.16
N
LIST_S2
Benign
0.76
T
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.13
T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
0.81
L
MutationTaster
Benign
1.0
N;N
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-0.53
N
REVEL
Benign
0.12
Sift
Benign
0.16
T
Sift4G
Benign
0.18
T
Polyphen
0.95
P
Vest4
0.072
MutPred
0.37
Loss of methylation at R46 (P = 0.0569);
MVP
0.80
MPC
0.42
ClinPred
0.56
D
GERP RS
-0.26
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.30
gMVP
0.56

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: rs11591147; hg19: chr1-55505647; COSMIC: COSV56162404; API