Genetic Variant PCSK9:c.657+82G>T (chr1-55052493-G-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_174936.4(PCSK9):c.657+82G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000622 in 1,607,962 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

PCSK9
NM_174936.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.169

Publications

12 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

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	Effect	Exon Rank	Protein
PCSK9	NM_174936.4	MANE Select	c.657+82G>T	intron	N/A	NP_777596.2
PCSK9	NM_001407240.1		c.780+82G>T	intron	N/A	NP_001394169.1
PCSK9	NM_001407241.1		c.657+82G>T	intron	N/A	NP_001394170.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.657+82G>T	intron	N/A	ENSP00000303208.5
PCSK9	ENST00000710286.1		c.1014+82G>T	intron	N/A	ENSP00000518176.1
PCSK9	ENST00000713786.1		c.780+82G>T	intron	N/A	ENSP00000519088.1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151412

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000964

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000673

AC:

AN:

1456550

Hom.:

Cov.:

AF XY:

0.0000677

AC XY:

AN XY:

724088

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33400

American (AMR)

AF:

0.00

AC:

AN:

44410

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26086

East Asian (EAS)

AF:

0.00

AC:

AN:

39580

South Asian (SAS)

AF:

0.00

AC:

AN:

85906

European-Finnish (FIN)

AF:

0.0000385

AC:

AN:

51884

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.0000775

AC:

AN:

1109366

Other (OTH)

AF:

0.000149

AC:

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000132

AC:

AN:

151412

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73854

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41356

American (AMR)

AF:

0.00

AC:

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4788

European-Finnish (FIN)

AF:

0.0000964

AC:

AN:

10378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67736

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

3873

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

1.3

(source)

DANN

Benign

0.67

PhyloP100

-0.17

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over