1-55052794-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_001407240.1(PCSK9):c.922+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.416 in 1,612,790 control chromosomes in the GnomAD database, including 144,840 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.49 ( 19713 hom., cov: 34)

Exomes 𝑓: 0.41 ( 125127 hom. )

Consequence

PCSK9
NM_001407240.1 splice_region, intron

Scores

Splicing: ADA: 0.001238

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 2.42

Publications

44 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant 1-55052794-A-G is Benign according to our data. Variant chr1-55052794-A-G is described in ClinVar as Benign. ClinVar VariationId is 262908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407240.1. 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.799+3A>G	splice_region intron	N/A	NP_777596.2
PCSK9	NM_001407240.1		c.922+3A>G	splice_region intron	N/A	NP_001394169.1
PCSK9	NM_001407241.1		c.799+3A>G	splice_region intron	N/A	NP_001394170.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.799+3A>G	splice_region intron	N/A	ENSP00000303208.5
PCSK9	ENST00000710286.1		c.1156+3A>G	splice_region intron	N/A	ENSP00000518176.1
PCSK9	ENST00000713786.1		c.922+3A>G	splice_region intron	N/A	ENSP00000519088.1

Frequencies

GnomAD3 genomes

AF:

0.485

AC:

73717

AN:

152018

Hom.:

19687

Cov.:

show subpopulations

Gnomad AFR

AF:

0.716

Gnomad AMI

AF:

0.392

Gnomad AMR

AF:

0.347

Gnomad ASJ

AF:

0.464

Gnomad EAS

AF:

0.259

Gnomad SAS

AF:

0.486

Gnomad FIN

AF:

0.450

Gnomad MID

AF:

0.522

Gnomad NFE

AF:

0.401

Gnomad OTH

AF:

0.446

GnomAD2 exomes

AF:

0.419

AC:

103408

AN:

247090

AF XY:

0.421

show subpopulations

Gnomad AFR exome

AF:

0.724

Gnomad AMR exome

AF:

0.302

Gnomad ASJ exome

AF:

0.469

Gnomad EAS exome

AF:

0.255

Gnomad FIN exome

AF:

0.450

Gnomad NFE exome

AF:

0.407

Gnomad OTH exome

AF:

0.404

GnomAD4 exome

AF:

0.409

AC:

596883

AN:

1460654

Hom.:

125127

Cov.:

AF XY:

0.411

AC XY:

298621

AN XY:

726638

show subpopulations

African (AFR)

AF:

0.725

AC:

24280

AN:

33478

American (AMR)

AF:

0.307

AC:

13734

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.468

AC:

12219

AN:

26130

East Asian (EAS)

AF:

0.268

AC:

10634

AN:

39694

South Asian (SAS)

AF:

0.491

AC:

42330

AN:

86240

European-Finnish (FIN)

AF:

0.444

AC:

23241

AN:

52378

Middle Eastern (MID)

AF:

0.456

AC:

2625

AN:

5754

European-Non Finnish (NFE)

AF:

0.398

AC:

442432

AN:

1111908

Other (OTH)

AF:

0.421

AC:

25388

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

22153

44305

66458

88610

110763

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13784

27568

41352

55136

68920

<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:

0.485

AC:

73797

AN:

152136

Hom.:

19713

Cov.:

AF XY:

0.482

AC XY:

35881

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.716

AC:

29748

AN:

41524

American (AMR)

AF:

0.347

AC:

5299

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.464

AC:

1608

AN:

3468

East Asian (EAS)

AF:

0.259

AC:

1334

AN:

5156

South Asian (SAS)

AF:

0.486

AC:

2336

AN:

4804

European-Finnish (FIN)

AF:

0.450

AC:

4776

AN:

10608

Middle Eastern (MID)

AF:

0.524

AC:

154

AN:

294

European-Non Finnish (NFE)

AF:

0.401

AC:

27247

AN:

67974

Other (OTH)

AF:

0.445

AC:

939

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1863

3725

5588

7450

9313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

650

1300

1950

2600

3250

<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:

0.434

Hom.:

31217

Bravo

AF:

0.484

Asia WGS

AF:

0.387

AC:

1348

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypercholesterolemia, autosomal dominant, 3 (4)

Hypercholesterolemia, familial, 1 (4)

not specified (4)

Familial hypercholesterolemia (2)

Cardiovascular phenotype (1)

Hypobetalipoproteinemia (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Mutation Taster

=83/17

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0012

dbscSNV1_RF

Benign

0.014

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

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over