chr1-55052643-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_174936.4(PCSK9):c.658-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 1,612,178 control chromosomes in the GnomAD database, including 154,963 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 15442 hom., cov: 34)

Exomes 𝑓: 0.43 ( 139521 hom. )

Consequence

PCSK9
NM_174936.4 splice_region, intron

Scores

Splicing: ADA: 0.00001414

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:18

Conservation

PhyloP100: -0.272

Publications

34 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 1-55052643-C-T is Benign according to our data. Variant chr1-55052643-C-T is described in ClinVar as Benign. ClinVar VariationId is 36672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.484 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.658-7C>T		splice_region_variant, 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.658-7C>T		splice_region_variant, intron_variant	Intron 4 of 11	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.446

AC:

67804

AN:

152030

Hom.:

15440

Cov.:

show subpopulations

Gnomad AFR

AF:

0.490

Gnomad AMI

AF:

0.600

Gnomad AMR

AF:

0.378

Gnomad ASJ

AF:

0.495

Gnomad EAS

AF:

0.224

Gnomad SAS

AF:

0.431

Gnomad FIN

AF:

0.468

Gnomad MID

AF:

0.525

Gnomad NFE

AF:

0.445

Gnomad OTH

AF:

0.433

GnomAD2 exomes

AF:

0.419

AC:

104152

AN:

248680

AF XY:

0.425

show subpopulations

Gnomad AFR exome

AF:

0.489

Gnomad AMR exome

AF:

0.319

Gnomad ASJ exome

AF:

0.501

Gnomad EAS exome

AF:

0.218

Gnomad FIN exome

AF:

0.463

Gnomad NFE exome

AF:

0.449

Gnomad OTH exome

AF:

0.421

GnomAD4 exome

AF:

0.434

AC:

634366

AN:

1460030

Hom.:

139521

Cov.:

AF XY:

0.436

AC XY:

316773

AN XY:

726170

show subpopulations

African (AFR)

AF:

0.496

AC:

16593

AN:

33466

American (AMR)

AF:

0.323

AC:

14447

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.506

AC:

13196

AN:

26094

East Asian (EAS)

AF:

0.234

AC:

9289

AN:

39678

South Asian (SAS)

AF:

0.446

AC:

38460

AN:

86180

European-Finnish (FIN)

AF:

0.454

AC:

23882

AN:

52614

Middle Eastern (MID)

AF:

0.465

AC:

2683

AN:

5766

European-Non Finnish (NFE)

AF:

0.441

AC:

489957

AN:

1111220

Other (OTH)

AF:

0.429

AC:

25859

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

21634

43268

64903

86537

108171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14750

29500

44250

59000

73750

<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:

0.446

AC:

67847

AN:

152148

Hom.:

15442

Cov.:

AF XY:

0.444

AC XY:

33048

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.490

AC:

20322

AN:

41512

American (AMR)

AF:

0.378

AC:

5783

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.495

AC:

1717

AN:

3472

East Asian (EAS)

AF:

0.223

AC:

1152

AN:

5158

South Asian (SAS)

AF:

0.430

AC:

2076

AN:

4826

European-Finnish (FIN)

AF:

0.468

AC:

4961

AN:

10602

Middle Eastern (MID)

AF:

0.534

AC:

157

AN:

294

European-Non Finnish (NFE)

AF:

0.445

AC:

30224

AN:

67972

Other (OTH)

AF:

0.430

AC:

908

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

2010

4020

6030

8040

10050

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

630

1260

1890

2520

3150

<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:

0.447

Hom.:

43619

Bravo

AF:

0.439

Asia WGS

AF:

0.337

AC:

1177

AN:

3478

EpiCase

AF:

0.455

EpiControl

AF:

0.456

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Benign:5

Aug 18, 2011

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 22, 2017

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 01, 2016

Iberoamerican FH Network

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

not specified

Benign:4

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 28, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypercholesterolemia, autosomal dominant, 3

Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Familial hypercholesterolemia

Benign:2

Jul 01, 2022

GENinCode PLC

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 09, 2023

Cohesion Phenomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Short fetal femur length

Uncertain:1

Phenosystems SA

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hypobetalipoproteinemia

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.1

(source)

DANN

Benign

0.56

PhyloP100

-0.27

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000014

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over