Variant rs11800265 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000302118.5(PCSK9):c.658-36G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0424 in 1,610,610 control chromosomes in the GnomAD database, including 1,652 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.039 ( 135 hom., cov: 34)

Exomes 𝑓: 0.043 ( 1517 hom. )

Consequence

PCSK9
ENST00000302118.5 intron

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:2

Conservation

PhyloP100: 0.877

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4 linkuse as main transcript	c.658-36G>A		intron_variant		ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5 linkuse as main transcript	c.658-36G>A		intron_variant		1	NM_174936.4	ENSP00000303208	P2	Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.0394

AC:

5998

AN:

152210

Hom.:

135

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0352

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.0359

Gnomad ASJ

AF:

0.0904

Gnomad EAS

AF:

0.0316

Gnomad SAS

AF:

0.0457

Gnomad FIN

AF:

0.0174

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.0427

Gnomad OTH

AF:

0.0535

GnomAD3 exomes

AF:

0.0417

AC:

10285

AN:

246884

Hom.:

293

AF XY:

0.0422

AC XY:

5664

AN XY:

134236

show subpopulations

Gnomad AFR exome

AF:

0.0340

Gnomad AMR exome

AF:

0.0285

Gnomad ASJ exome

AF:

0.0947

Gnomad EAS exome

AF:

0.0317

Gnomad SAS exome

AF:

0.0474

Gnomad FIN exome

AF:

0.0215

Gnomad NFE exome

AF:

0.0455

Gnomad OTH exome

AF:

0.0510

GnomAD4 exome

AF:

0.0427

AC:

62301

AN:

1458282

Hom.:

1517

Cov.:

AF XY:

0.0429

AC XY:

31113

AN XY:

724930

show subpopulations

Gnomad4 AFR exome

AF:

0.0365

Gnomad4 AMR exome

AF:

0.0294

Gnomad4 ASJ exome

AF:

0.0940

Gnomad4 EAS exome

AF:

0.0274

Gnomad4 SAS exome

AF:

0.0445

Gnomad4 FIN exome

AF:

0.0235

Gnomad4 NFE exome

AF:

0.0429

Gnomad4 OTH exome

AF:

0.0471

GnomAD4 genome

AF:

0.0394

AC:

6006

AN:

152328

Hom.:

135

Cov.:

AF XY:

0.0378

AC XY:

2814

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0353

Gnomad4 AMR

AF:

0.0359

Gnomad4 ASJ

AF:

0.0904

Gnomad4 EAS

AF:

0.0315

Gnomad4 SAS

AF:

0.0455

Gnomad4 FIN

AF:

0.0174

Gnomad4 NFE

AF:

0.0427

Gnomad4 OTH

AF:

0.0544

Alfa

AF:

0.0476

Hom.:

Bravo

AF:

0.0417

Asia WGS

AF:

0.0500

AC:

174

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Mar 01, 2016

- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

2.9

DANN

Benign

0.74

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over