Genetic Variant PCSK9:c.1863+689C>T (chr1-55062245-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_174936.4(PCSK9):c.1863+689C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.828 in 152,278 control chromosomes in the GnomAD database, including 52,417 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.83 ( 52417 hom., cov: 35)

Consequence

PCSK9
NM_174936.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.501

Publications

4 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.1863+689C>T		intron_variant	Intron 11 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.1863+689C>T		intron_variant	Intron 11 of 11	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.828

AC:

126039

AN:

152160

Hom.:

52385

Cov.:

show subpopulations

Gnomad AFR

AF:

0.779

Gnomad AMI

AF:

0.874

Gnomad AMR

AF:

0.881

Gnomad ASJ

AF:

0.813

Gnomad EAS

AF:

0.991

Gnomad SAS

AF:

0.887

Gnomad FIN

AF:

0.821

Gnomad MID

AF:

0.864

Gnomad NFE

AF:

0.830

Gnomad OTH

AF:

0.853

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.828

AC:

126126

AN:

152278

Hom.:

52417

Cov.:

AF XY:

0.830

AC XY:

61809

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.779

AC:

32374

AN:

41548

American (AMR)

AF:

0.881

AC:

13473

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.813

AC:

2824

AN:

3472

East Asian (EAS)

AF:

0.991

AC:

5140

AN:

5188

South Asian (SAS)

AF:

0.887

AC:

4282

AN:

4828

European-Finnish (FIN)

AF:

0.821

AC:

8714

AN:

10610

Middle Eastern (MID)

AF:

0.864

AC:

254

AN:

294

European-Non Finnish (NFE)

AF:

0.830

AC:

56460

AN:

68012

Other (OTH)

AF:

0.854

AC:

1808

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1156

2312

3469

4625

5781

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:

0.830

Hom.:

17379

Bravo

AF:

0.831

Asia WGS

AF:

0.920

AC:

3201

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.35

(source)

DANN

Benign

0.28

PhyloP100

-0.50

Mutation Taster

=100/0

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over