chr1-55057505-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_174936.4(PCSK9):c.1171C>A(p.His391Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000131 in 1,611,392 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H391H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000068 ( 1 hom. )

Consequence

PCSK9
NM_174936.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 4.77

Publications

10 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24483848).

BP6

Variant 1-55057505-C-A is Benign according to our data. Variant chr1-55057505-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 496557.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000735 (112/152328) while in subpopulation AFR AF = 0.00267 (111/41568). AF 95% confidence interval is 0.00227. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.1171C>A	p.His391Asn	missense	Exon 7 of 12	NP_777596.2
PCSK9	NM_001407240.1		c.1294C>A	p.His432Asn	missense	Exon 8 of 13	NP_001394169.1
PCSK9	NM_001407241.1		c.1171C>A	p.His391Asn	missense	Exon 7 of 12	NP_001394170.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.1171C>A	p.His391Asn	missense	Exon 7 of 12	ENSP00000303208.5
PCSK9	ENST00000710286.1		c.1528C>A	p.His510Asn	missense	Exon 7 of 12	ENSP00000518176.1
PCSK9	ENST00000713786.1		c.1294C>A	p.His432Asn	missense	Exon 8 of 13	ENSP00000519088.1

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00268

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000163

AC:

AN:

245980

AF XY:

0.000105

show subpopulations

Gnomad AFR exome

AF:

0.00241

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000679

AC:

AN:

1459064

Hom.:

Cov.:

AF XY:

0.0000661

AC XY:

AN XY:

725660

show subpopulations

African (AFR)

AF:

0.00278

AC:

AN:

33414

American (AMR)

AF:

0.0000225

AC:

AN:

44530

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39602

South Asian (SAS)

AF:

0.00

AC:

AN:

85912

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52742

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5346

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111162

Other (OTH)

AF:

0.0000830

AC:

AN:

60262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.000735

AC:

112

AN:

152328

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00267

AC:

111

AN:

41568

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000383

Hom.:

Bravo

AF:

0.000884

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000206

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3

Uncertain:1Benign:1

Jul 13, 2021

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Aug 06, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PCSK9 c.1171C>A (p.His391Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 245980 control chromosomes. The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (3.8e-05). c.1171C>A has been reported in patients with hypocholesterolemia, mainly of African origin (Kotowski_2006, Lange_2014), as well as in individuals with apparently normal blood pressure (Tran_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19191301, 17971861, 24278757, 16465619, 24507775, 25904937). ClinVar contains an entry for this variant (Variation ID: 496557). Based on the evidence outlined above, the variant was classified as likely benign.

Familial hypercholesterolemia

Benign:1

Jan 01, 2022

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.62

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.023

MetaRNN

Benign

0.24

MetaSVM

Uncertain

0.43

MutationAssessor

Pathogenic

5.0

PhyloP100

4.8

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-5.4

REVEL

Pathogenic

0.67

Sift

Benign

0.083

Sift4G

Benign

0.11

Polyphen

1.0

Vest4

0.78

MVP

0.86

MPC

0.89

ClinPred

0.24

GERP RS

3.2

Varity_R

0.96

gMVP

0.91

Mutation Taster

=55/45

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over