rs72646509

chr1-55056028-C-Achr1-55056028-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_174936.4(PCSK9):c.835C>A(p.Pro279Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000237 in 1,610,234 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P279L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (2 hom.)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 3.85

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009918392).
• BP6: Variant 1-55056028-C-A is Benign according to our data. Variant chr1-55056028-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 375846.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=3, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 173 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4	c.835C>A	p.Pro279Thr	missense_variant	6/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5	c.835C>A	p.Pro279Thr	missense_variant	6/12	1	NM_174936.4	P2

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 173 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00384

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: 0.00144

GnomAD3 exomes AF: 0.000308 AC: 75 AN: 243220 Hom.: 0 AF XY: 0.000212 AC XY: 28 AN XY: 132360

Gnomad AFR exome AF: 0.00355

Gnomad AMR exome AF: 0.000379

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: 0.0000460

Gnomad OTH exome AF: 0.000337

GnomAD4 exome AF: 0.000142 AC: 207 AN: 1457938 Hom.: 2 Cov.: 32 AF XY: 0.000124 AC XY: 90 AN XY: 724680

Gnomad4 AFR exome AF: 0.00401

Gnomad4 AMR exome AF: 0.000404

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: 0.0000243

Gnomad4 OTH exome AF: 0.000366

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74466

Gnomad4 AFR AF: 0.00387

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: 0.00142

Alfa AF: 0.000302 Hom.: 0

Bravo AF: 0.00146

ESP6500AA AF: 0.00341 AC: 15

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000371 AC: 45

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000595

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Uncertain:1 Benign:1

Uncertain significance, 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: Damaging -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 22, 2017	Variant summary: The PCSK9 c.835C>A (p.Pro279Thr) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 41/94810 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.004103 (31/7556). This frequency is about 205 times the estimated maximal expected allele frequency of a pathogenic PCSK9 variant (0.00002), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant has been reported in the literature as a SNP and has been observed at equal frequencies both in patients with low LDL-C and high LDL-C. Therefore, its role in the pathophysiology of Familial Hypercholesterolemia and early onset CAD is suspect. One clinical diagnostic laboratory classified this variant as uncertain significance. Taken together, due to the relatively high frequency of the variant in the control population, this variant has been classified as benign. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2020

This alteration is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 02, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.0099	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.38
MVP		0.90
MPC		0.70
ClinPred		0.033	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.50

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

Other links and lift over

dbSNP: rs72646509; hg19: chr1-55521701;