rs141502002

Variant names:

• chr1-55058549-C-T
• rs141502002
• NM_174936.4:c.1405C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_174936.4(PCSK9):​c.1405C>T​(p.Arg469Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000481 in 1,612,150 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. R469Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (3 hom.)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:8
• Conservation: PhyloP100: 0.0310
• Publications: 33 publications found

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]

PCSK9 Gene-Disease associations (from GenCC):

• hypercholesterolemia, autosomal dominant, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 11 uncertain in NM_174936.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.011399835).
• BP6: Variant 1-55058549-C-T is Benign according to our data. Variant chr1-55058549-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 201128.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00253 (385/152288) while in subpopulation AFR AF = 0.00883 (367/41564). AF 95% confidence interval is 0.00809. There are 4 homozygotes in GnomAd4. There are 176 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174936.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	NM_174936.4	MANE Select	c.1405C>T	p.Arg469Trp	missense	Exon 9 of 12	NP_777596.2
	PCSK9	NM_001407240.1		c.1528C>T	p.Arg510Trp	missense	Exon 10 of 13	NP_001394169.1
	PCSK9	NM_001407241.1		c.1405C>T	p.Arg469Trp	missense	Exon 9 of 12	NP_001394170.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.1405C>T	p.Arg469Trp	missense	Exon 9 of 12	ENSP00000303208.5
	PCSK9	ENST00000710286.1		c.1762C>T	p.Arg588Trp	missense	Exon 9 of 12	ENSP00000518176.1
	PCSK9	ENST00000713786.1		c.1528C>T	p.Arg510Trp	missense	Exon 10 of 13	ENSP00000519088.1

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 386 AN: 152170 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00888

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.0000735

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000605 AC: 152 AN: 251352 AF XY: 0.000427

Gnomad AFR exome AF: 0.00837

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000268 AC: 391 AN: 1459862 Hom.: 3 Cov.: 86 AF XY: 0.000256 AC XY: 186 AN XY: 726236

African (AFR) AF: 0.00868 AC: 290 AN: 33414

American (AMR) AF: 0.000335 AC: 15 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.000241 AC: 1 AN: 4144

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1111996

Other (OTH) AF: 0.000664 AC: 40 AN: 60224

GnomAD4 genome AF: 0.00253 AC: 385 AN: 152288 Hom.: 4 Cov.: 33 AF XY: 0.00236 AC XY: 176 AN XY: 74452

African (AFR) AF: 0.00883 AC: 367 AN: 41564

American (AMR) AF: 0.000588 AC: 9 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000797 Hom.: 2

Bravo AF: 0.00277

ESP6500AA AF: 0.00794 AC: 35

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000700 AC: 85

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Hypercholesterolemia, autosomal dominant, 3 (3)
1	1	1	Hypercholesterolemia, familial, 1 (3)
-	-	2	Familial hypercholesterolemia (2)
-	1	1	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Hypobetalipoproteinemia (1)
-	-	1	not provided (1)
-	1	-	PCSK9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.031
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.24
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.71
MVP		0.84
MPC		0.24
ClinPred		0.017	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.38
gMVP		0.80
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs141502002; hg19: chr1-55524222; COSMIC: COSV56160629;