rs28362277

chr1-55061549-A-Cchr1-55061549-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_174936.4(PCSK9):c.1856A>C(p.Gln619Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000735 in 1,596,476 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0040 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (7 hom.)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:8
• Conservation: PhyloP100: -1.27

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055326223).
• BP6: Variant 1-55061549-A-C is Benign according to our data. Variant chr1-55061549-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 375852.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Likely_benign=2, Uncertain_significance=1}. Variant chr1-55061549-A-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00404 (615/152324) while in subpopulation AFR AF= 0.0144 (599/41582). AF 95% confidence interval is 0.0135. There are 9 homozygotes in gnomad4. There are 289 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 615 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4	c.1856A>C	p.Gln619Pro	missense_variant	11/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5	c.1856A>C	p.Gln619Pro	missense_variant	11/12	1	NM_174936.4	P2

Frequencies

GnomAD3 genomes AF: 0.00404 AC: 615 AN: 152206 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000961 AC: 207 AN: 215432 Hom.: 0 AF XY: 0.000681 AC XY: 79 AN XY: 116068

Gnomad AFR exome AF: 0.0151

Gnomad AMR exome AF: 0.000226

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000314

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000386 AC: 558 AN: 1444152 Hom.: 7 Cov.: 32 AF XY: 0.000310 AC XY: 222 AN XY: 716466

Gnomad4 AFR exome AF: 0.0153

Gnomad4 AMR exome AF: 0.000381

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: 0.00000634

Gnomad4 OTH exome AF: 0.000452

GnomAD4 genome AF: 0.00404 AC: 615 AN: 152324 Hom.: 9 Cov.: 33 AF XY: 0.00388 AC XY: 289 AN XY: 74498

Gnomad4 AFR AF: 0.0144

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000742 Hom.: 0

Bravo AF: 0.00461

ESP6500AA AF: 0.0135 AC: 59

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00102 AC: 123

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Benign:3

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subject mutated among 2600 FH index cases screened = 1 / Software predictions: Benign -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 28, 2016	Variant summary: The PCSK9 c.1856A>C variant affects a non-conserved nucleotide, resulting in amino acid change from Gln to Pro. 3/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). This variant was found in 101/54678 control chromosomes at a frequency of 0.0018472, which is about 99 times the maximal expected frequency of a pathogenic PCSK9 allele (0.0000188), suggesting this variant is benign. This variant has been found only in Africans, including African controls (101/5202 ExAC African chromosomes) and both high and low LDL African patients in the literature, at a similar allele frequency (1.5-2%). Taken together, based on the prevalence of this variant in general population, this variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 23, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2021	This variant is associated with the following publications: (PMID: 16465619, 17971861) -

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2016

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. -

Familial hypercholesterolemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	3.1
Dann	Benign	0.61
DEOGEN2	Benign	0.072	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.22
Sift	Benign	0.25	T
Sift4G	Benign	0.32	T
Polyphen		0.054	B
Vest4		0.26
MVP		0.46
MPC		0.29
ClinPred		0.0056	T
GERP RS		-0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs28362277; hg19: chr1-55527222;