rs11800243

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_174936.4(PCSK9):c.657+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0425 in 1,613,596 control chromosomes in the GnomAD database, including 1,669 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.040 ( 150 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1519 hom. )

Consequence

PCSK9
NM_174936.4 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:16

Conservation

PhyloP100: -0.163

Publications

14 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 1-55052420-G-A is Benign according to our data. Variant chr1-55052420-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 262906.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

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	UniProt
PCSK9	NM_174936.4	MANE Select	c.657+9G>A	intron	N/A	NP_777596.2
PCSK9	NM_001407240.1		c.780+9G>A	intron	N/A	NP_001394169.1	A0AAQ5BGX4
PCSK9	NM_001407241.1		c.657+9G>A	intron	N/A	NP_001394170.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.657+9G>A	intron	N/A	ENSP00000303208.5	Q8NBP7-1
PCSK9	ENST00000710286.1		c.1014+9G>A	intron	N/A	ENSP00000518176.1	A0AA34QVH0
PCSK9	ENST00000713786.1		c.780+9G>A	intron	N/A	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes

AF:

0.0403

AC:

6132

AN:

152080

Hom.:

150

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0393

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.0355

Gnomad ASJ

AF:

0.0931

Gnomad EAS

AF:

0.0299

Gnomad SAS

AF:

0.0450

Gnomad FIN

AF:

0.0173

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.0424

Gnomad OTH

AF:

0.0546

GnomAD2 exomes

AF:

0.0419

AC:

10495

AN:

250622

AF XY:

0.0423

show subpopulations

Gnomad AFR exome

AF:

0.0395

Gnomad AMR exome

AF:

0.0283

Gnomad ASJ exome

AF:

0.0980

Gnomad EAS exome

AF:

0.0293

Gnomad FIN exome

AF:

0.0217

Gnomad NFE exome

AF:

0.0454

Gnomad OTH exome

AF:

0.0517

GnomAD4 exome

AF:

0.0427

AC:

62460

AN:

1461398

Hom.:

1519

Cov.:

AF XY:

0.0429

AC XY:

31197

AN XY:

727004

show subpopulations

African (AFR)

AF:

0.0413

AC:

1384

AN:

33480

American (AMR)

AF:

0.0294

AC:

1314

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0973

AC:

2544

AN:

26136

East Asian (EAS)

AF:

0.0263

AC:

1044

AN:

39700

South Asian (SAS)

AF:

0.0439

AC:

3787

AN:

86254

European-Finnish (FIN)

AF:

0.0236

AC:

1248

AN:

52968

Middle Eastern (MID)

AF:

0.124

AC:

716

AN:

5764

European-Non Finnish (NFE)

AF:

0.0428

AC:

47571

AN:

1111992

Other (OTH)

AF:

0.0472

AC:

2852

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

3829

7658

11488

15317

19146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1792

3584

5376

7168

8960

<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:

0.0403

AC:

6139

AN:

152198

Hom.:

150

Cov.:

AF XY:

0.0386

AC XY:

2874

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0394

AC:

1637

AN:

41522

American (AMR)

AF:

0.0355

AC:

542

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0931

AC:

323

AN:

3470

East Asian (EAS)

AF:

0.0298

AC:

154

AN:

5174

South Asian (SAS)

AF:

0.0449

AC:

216

AN:

4814

European-Finnish (FIN)

AF:

0.0173

AC:

184

AN:

10612

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0424

AC:

2882

AN:

68006

Other (OTH)

AF:

0.0550

AC:

116

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

287

574

861

1148

1435

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<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:

0.0448

Hom.:

155

Bravo

AF:

0.0428

Asia WGS

AF:

0.0490

AC:

171

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Hypercholesterolemia, autosomal dominant, 3 (4)

Hypercholesterolemia, familial, 1 (4)

Familial hypercholesterolemia (2)

Cardiovascular phenotype (1)

Hypobetalipoproteinemia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

4.4

(source)

DANN

Benign

0.52

PhyloP100

-0.16

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

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

Computational scores

Splicing

Publications

Other links and lift over