rs562556

Variant names:

• chr1-55058564-G-A
• rs562556
• NM_174936.4:c.1420G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_174936.4(PCSK9):​c.1420G>A​(p.Val474Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.833 in 1,611,942 control chromosomes in the GnomAD database, including 560,455 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. V474V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.83 (52804 hom., cov: 31)
  • Exomes 𝑓: 0.83 (507651 hom.)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.619
• Publications: 134 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 11 uncertain in NM_174936.4
• BP4: Computational evidence support a benign effect (MetaRNN=7.670029E-7).
• BP6: Variant 1-55058564-G-A is Benign according to our data. Variant chr1-55058564-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 201124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	NM_174936.4	MANE Select	c.1420G>A	p.Val474Ile	missense	Exon 9 of 12	NP_777596.2
	PCSK9	NM_001407240.1		c.1543G>A	p.Val515Ile	missense	Exon 10 of 13	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.1420G>A	p.Val474Ile	missense	Exon 9 of 12	NP_001394170.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.1420G>A	p.Val474Ile	missense	Exon 9 of 12	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.1777G>A	p.Val593Ile	missense	Exon 9 of 12	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.1543G>A	p.Val515Ile	missense	Exon 10 of 13	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes AF: 0.832 AC: 126474 AN: 152014 Hom.: 52772 Cov.: 31

Gnomad AFR AF: 0.789

Gnomad AMI AF: 0.874

Gnomad AMR AF: 0.883

Gnomad ASJ AF: 0.815

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.888

Gnomad FIN AF: 0.822

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.831

Gnomad OTH AF: 0.856

GnomAD2 exomes AF: 0.857 AC: 215212 AN: 251218 AF XY: 0.854

Gnomad AFR exome AF: 0.787

Gnomad AMR exome AF: 0.915

Gnomad ASJ exome AF: 0.814

Gnomad EAS exome AF: 0.993

Gnomad FIN exome AF: 0.826

Gnomad NFE exome AF: 0.832

Gnomad OTH exome AF: 0.860

GnomAD4 exome AF: 0.833 AC: 1216353 AN: 1459810 Hom.: 507651 Cov.: 86 AF XY: 0.834 AC XY: 605946 AN XY: 726216

African (AFR) AF: 0.790 AC: 26389 AN: 33410

American (AMR) AF: 0.911 AC: 40737 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.813 AC: 21249 AN: 26136

East Asian (EAS) AF: 0.978 AC: 38846 AN: 39700

South Asian (SAS) AF: 0.874 AC: 75273 AN: 86172

European-Finnish (FIN) AF: 0.829 AC: 44182 AN: 53314

Middle Eastern (MID) AF: 0.873 AC: 3614 AN: 4142

European-Non Finnish (NFE) AF: 0.824 AC: 915724 AN: 1111990

Other (OTH) AF: 0.836 AC: 50339 AN: 60224

GnomAD4 genome AF: 0.832 AC: 126561 AN: 152132 Hom.: 52804 Cov.: 31 AF XY: 0.834 AC XY: 61987 AN XY: 74358

African (AFR) AF: 0.789 AC: 32734 AN: 41480

American (AMR) AF: 0.883 AC: 13514 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.815 AC: 2828 AN: 3472

East Asian (EAS) AF: 0.991 AC: 5109 AN: 5156

South Asian (SAS) AF: 0.887 AC: 4288 AN: 4832

European-Finnish (FIN) AF: 0.822 AC: 8702 AN: 10580

Middle Eastern (MID) AF: 0.864 AC: 254 AN: 294

European-Non Finnish (NFE) AF: 0.831 AC: 56523 AN: 67992

Other (OTH) AF: 0.858 AC: 1812 AN: 2112

Alfa AF: 0.832 Hom.: 242171

Bravo AF: 0.834

TwinsUK AF: 0.821 AC: 3045

ALSPAC AF: 0.807 AC: 3110

ESP6500AA AF: 0.787 AC: 3468

ESP6500EA AF: 0.833 AC: 7168

ExAC AF: 0.854 AC: 103723

Asia WGS AF: 0.923 AC: 3208 AN: 3476

EpiCase AF: 0.829

EpiControl AF: 0.825

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Hypercholesterolemia, autosomal dominant, 3 (5)
-	-	4	Hypercholesterolemia, familial, 1 (4)
-	-	3	not specified (3)
-	-	2	Familial hypercholesterolemia (2)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypobetalipoproteinemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.036
DANN	Benign	0.83
DEOGEN2	Benign	0.087	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	7.7e-7	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.62
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.051
Sift	Benign	0.41	T
Sift4G	Benign	0.19	T
Polyphen		0.013	B
Vest4		0.025
MPC		0.18
ClinPred		0.015	T
GERP RS		-8.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.049
gMVP		0.51
Mutation Taster		=99/1	polymorphism (auto)

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: rs562556; hg19: chr1-55524237; COSMIC: COSV56163657;