Variant 1-55056233-A-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_174936.4(PCSK9):c.996+44A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.37 ( 16 hom., cov: 0)

Exomes 𝑓: 0.50 ( 880 hom. )

Failed GnomAD Quality Control

Consequence

PCSK9
NM_174936.4 intron

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.84

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:

PCSK9 (HGNC:):

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=-0.92).

BA1

GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.52 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.996+44A>G		intron_variant		ENST00000302118.5	NP_777596.2	Q8NBP7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5 linkuse as main transcript	c.996+44A>G		intron_variant		1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

910

AN:

2456

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.410

Gnomad AMR

AF:

0.240

Gnomad ASJ

AF:

0.0278

Gnomad EAS

AF:

0.500

Gnomad SAS

AF:

0.417

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0556

Gnomad OTH

AF:

0.233

GnomAD3 exomes

AF:

0.0211

AC:

175

AN:

8282

Hom.:

AF XY:

0.0208

AC XY:

AN XY:

4036

show subpopulations

Gnomad AFR exome

AF:

0.0776

Gnomad AMR exome

AF:

0.0147

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0500

Gnomad SAS exome

AF:

0.0495

Gnomad FIN exome

AF:

0.0186

Gnomad NFE exome

AF:

0.0165

Gnomad OTH exome

AF:

0.0357

GnomAD4 exome

AF:

0.496

AC:

21218

AN:

42746

Hom.:

880

Cov.:

AF XY:

0.495

AC XY:

9913

AN XY:

20042

show subpopulations

Gnomad4 AFR exome

AF:

0.513

Gnomad4 AMR exome

AF:

0.467

Gnomad4 ASJ exome

AF:

0.248

Gnomad4 EAS exome

AF:

0.507

Gnomad4 SAS exome

AF:

0.547

Gnomad4 FIN exome

AF:

0.500

Gnomad4 NFE exome

AF:

0.497

Gnomad4 OTH exome

AF:

0.481

GnomAD4 genome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.371

AC:

912

AN:

2458

Hom.:

Cov.:

AF XY:

0.376

AC XY:

437

AN XY:

1162

show subpopulations

Gnomad4 AFR

AF:

0.411

Gnomad4 AMR

AF:

0.245

Gnomad4 ASJ

AF:

0.0278

Gnomad4 EAS

AF:

0.500

Gnomad4 SAS

AF:

0.400

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0556

Gnomad4 OTH

AF:

0.233

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.25

DANN

Benign

0.13

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