rs1060500656

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_174936.4(PCSK9):​c.1858G>A​(p.Glu620Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E620E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

PCSK9
NM_174936.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.13
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.24893677).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PCSK9NM_174936.4 linkuse as main transcriptc.1858G>A p.Glu620Lys missense_variant 11/12 ENST00000302118.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PCSK9ENST00000302118.5 linkuse as main transcriptc.1858G>A p.Glu620Lys missense_variant 11/121 NM_174936.4 P2Q8NBP7-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 29, 2016This sequence change replaces glutamic acid with lysine at codon 620 of the PCSK9 protein (p.Glu620Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. While this variant is not present in population databases (ExAC no frequency), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in an individual with a PCSK9-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.077
BayesDel_addAF
Benign
0.0018
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.19
T
Eigen
Benign
-0.43
Eigen_PC
Benign
-0.38
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.78
T
M_CAP
Benign
0.074
D
MetaRNN
Benign
0.25
T
MetaSVM
Benign
-0.90
T
MutationAssessor
Uncertain
2.5
M
MutationTaster
Benign
0.97
D;N
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-0.76
N
REVEL
Benign
0.15
Sift
Benign
0.20
T
Sift4G
Benign
0.39
T
Polyphen
0.22
B
Vest4
0.34
MutPred
0.33
Gain of methylation at E620 (P = 0.0124);
MVP
0.82
MPC
0.30
ClinPred
0.45
T
GERP RS
1.8
Varity_R
0.19
gMVP
0.71

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1060500656; hg19: chr1-55527224; API