Genetic Variant PCSK9:c.657+114dupC (chr1-55052517-A-AC) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_174936.4(PCSK9):c.657+114dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0055 ( 5 hom., cov: 0)

Exomes 𝑓: 0.0068 ( 52 hom. )

Consequence

PCSK9
NM_174936.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.574

Publications

3 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 -8 ACMG points.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00549 (831/151504) while in subpopulation SAS AF = 0.02 (96/4802). AF 95% confidence interval is 0.0168. There are 5 homozygotes in GnomAd4. There are 455 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.657+114dupC		intron_variant	Intron 4 of 11	ENST00000302118.5	NP_777596.2	Q8NBP7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5 link	c.657+106_657+107insC		intron_variant	Intron 4 of 11	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.00550

AC:

832

AN:

151386

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00156

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00446

Gnomad ASJ

AF:

0.00953

Gnomad EAS

AF:

0.000585

Gnomad SAS

AF:

0.0198

Gnomad FIN

AF:

0.00511

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.00738

Gnomad OTH

AF:

0.00528

GnomAD4 exome

AF:

0.00682

AC:

9848

AN:

1444146

Hom.:

Cov.:

AF XY:

0.00730

AC XY:

5234

AN XY:

717124

show subpopulations

African (AFR)

AF:

0.00134

AC:

AN:

32826

American (AMR)

AF:

0.00428

AC:

188

AN:

43914

Ashkenazi Jewish (ASJ)

AF:

0.00764

AC:

197

AN:

25786

East Asian (EAS)

AF:

0.0000764

AC:

AN:

39292

South Asian (SAS)

AF:

0.0182

AC:

1552

AN:

85240

European-Finnish (FIN)

AF:

0.00513

AC:

264

AN:

51416

Middle Eastern (MID)

AF:

0.00718

AC:

AN:

5574

European-Non Finnish (NFE)

AF:

0.00652

AC:

7175

AN:

1100468

Other (OTH)

AF:

0.00646

AC:

385

AN:

59630

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

527

1054

1580

2107

2634

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

276

552

828

1104

1380

<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:

0.00549

AC:

831

AN:

151504

Hom.:

Cov.:

AF XY:

0.00614

AC XY:

455

AN XY:

74068

show subpopulations

African (AFR)

AF:

0.00156

AC:

AN:

41082

American (AMR)

AF:

0.00445

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00953

AC:

AN:

3464

East Asian (EAS)

AF:

0.000586

AC:

AN:

5120

South Asian (SAS)

AF:

0.0200

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00511

AC:

AN:

10566

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00738

AC:

501

AN:

67894

Other (OTH)

AF:

0.00523

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

127

170

212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.00378

Hom.:

941

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.57

Mutation Taster

=100/0

polymorphism

(source)

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

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1-55052517-ACC-ACCC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over