Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_174936.4(PCSK9):c.1380A>G(p.Val460Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.833 in 1,612,026 control chromosomes in the GnomAD database, including 560,530 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.83 ( 52811 hom., cov: 32)

Exomes 𝑓: 0.83 ( 507719 hom. )

Consequence

PCSK9
NM_174936.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: 1.50

Publications

40 publications found

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]

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

PCSK9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.134).

BP6

Variant 1-55058524-A-G is Benign according to our data. Variant chr1-55058524-A-G is described in ClinVar as Benign. ClinVar VariationId is 201126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.5 with no splicing effect.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCSK9	NM_174936.4	MANE Select	c.1380A>G	p.Val460Val	synonymous	Exon 9 of 12	NP_777596.2
PCSK9	NM_001407240.1		c.1503A>G	p.Val501Val	synonymous	Exon 10 of 13	NP_001394169.1
PCSK9	NM_001407241.1		c.1380A>G	p.Val460Val	synonymous	Exon 9 of 12	NP_001394170.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.1380A>G	p.Val460Val	synonymous	Exon 9 of 12	ENSP00000303208.5
PCSK9	ENST00000710286.1		c.1737A>G	p.Val579Val	synonymous	Exon 9 of 12	ENSP00000518176.1
PCSK9	ENST00000713786.1		c.1503A>G	p.Val501Val	synonymous	Exon 10 of 13	ENSP00000519088.1

Frequencies

GnomAD3 genomes

AF:

0.832

AC:

126484

AN:

152014

Hom.:

52779

Cov.:

show subpopulations

Gnomad AFR

AF:

0.790

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:

215309

AN:

251326

AF XY:

0.854

show subpopulations

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:

0.827

Gnomad NFE exome

AF:

0.832

Gnomad OTH exome

AF:

0.860

GnomAD4 exome

AF:

0.833

AC:

1216466

AN:

1459894

Hom.:

507719

Cov.:

AF XY:

0.834

AC XY:

605989

AN XY:

726242

show subpopulations

African (AFR)

AF:

0.790

AC:

26391

AN:

33412

American (AMR)

AF:

0.911

AC:

40739

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.813

AC:

21249

AN:

26136

East Asian (EAS)

AF:

0.979

AC:

38847

AN:

39700

South Asian (SAS)

AF:

0.874

AC:

75276

AN:

86172

European-Finnish (FIN)

AF:

0.829

AC:

44251

AN:

53392

Middle Eastern (MID)

AF:

0.873

AC:

3618

AN:

4146

European-Non Finnish (NFE)

AF:

0.824

AC:

915752

AN:

1111988

Other (OTH)

AF:

0.836

AC:

50343

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

13513

27026

40540

54053

67566

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20992

41984

62976

83968

104960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.832

AC:

126571

AN:

152132

Hom.:

52811

Cov.:

AF XY:

0.834

AC XY:

61993

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.789

AC:

32742

AN:

41480

American (AMR)

AF:

0.883

AC:

13520

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.815

AC:

2828

AN:

3472

East Asian (EAS)

AF:

0.991

AC:

5104

AN:

5152

South Asian (SAS)

AF:

0.888

AC:

4281

AN:

4820

European-Finnish (FIN)

AF:

0.822

AC:

8708

AN:

10590

Middle Eastern (MID)

AF:

0.864

AC:

254

AN:

294

European-Non Finnish (NFE)

AF:

0.831

AC:

56522

AN:

67990

Other (OTH)

AF:

0.858

AC:

1815

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

1107

2215

3322

4430

5537

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

884

1768

2652

3536

4420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.831

Hom.:

145375

Bravo

AF:

0.834

Asia WGS

AF:

0.923

AC:

3209

AN:

3476

EpiCase

AF:

0.829

EpiControl

AF:

0.825

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypercholesterolemia, autosomal dominant, 3 (5)

Hypercholesterolemia, familial, 1 (4)

not specified (3)

Familial hypercholesterolemia (2)

not provided (2)

Cardiovascular phenotype (1)

Hypobetalipoproteinemia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

8.9

(source)

DANN

Benign

0.25

PhyloP100

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Mutation Taster

=92/8

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over