Variant rs45439391 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_174936.4(PCSK9):c.1681+63C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0509 in 1,529,080 control chromosomes in the GnomAD database, including 2,203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.052 ( 233 hom., cov: 33)

Exomes 𝑓: 0.051 ( 1970 hom. )

Consequence

PCSK9
NM_174936.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.486

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 1-55059726-C-T is Benign according to our data. Variant chr1-55059726-C-T is described in ClinVar as [Benign]. Clinvar id is 265947.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-55059726-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0595 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4 linkuse as main transcript	c.1681+63C>T		intron_variant		ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5 linkuse as main transcript	c.1681+63C>T		intron_variant		1	NM_174936.4	P2	Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.0520

AC:

7907

AN:

152204

Hom.:

233

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0615

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.0427

Gnomad ASJ

AF:

0.114

Gnomad EAS

AF:

0.0511

Gnomad SAS

AF:

0.0627

Gnomad FIN

AF:

0.0164

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.0491

Gnomad OTH

AF:

0.0631

GnomAD4 exome

AF:

0.0508

AC:

69982

AN:

1376758

Hom.:

1970

AF XY:

0.0514

AC XY:

34802

AN XY:

677392

show subpopulations

Gnomad4 AFR exome

AF:

0.0634

Gnomad4 AMR exome

AF:

0.0345

Gnomad4 ASJ exome

AF:

0.117

Gnomad4 EAS exome

AF:

0.0416

Gnomad4 SAS exome

AF:

0.0625

Gnomad4 FIN exome

AF:

0.0231

Gnomad4 NFE exome

AF:

0.0496

Gnomad4 OTH exome

AF:

0.0576

GnomAD4 genome

AF:

0.0520

AC:

7916

AN:

152322

Hom.:

233

Cov.:

AF XY:

0.0501

AC XY:

3730

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0615

Gnomad4 AMR

AF:

0.0427

Gnomad4 ASJ

AF:

0.114

Gnomad4 EAS

AF:

0.0512

Gnomad4 SAS

AF:

0.0623

Gnomad4 FIN

AF:

0.0164

Gnomad4 NFE

AF:

0.0491

Gnomad4 OTH

AF:

0.0634

Alfa

AF:

0.0534

Hom.:

Bravo

AF:

0.0552

Asia WGS

AF:

0.0580

AC:

203

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Benign:1

Benign, criteria provided, single submitter

research

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Mar 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.84

DANN

Benign

0.56

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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