Variant rs11806638 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_174936.4(PCSK9):c.657+76C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0695 in 1,606,636 control chromosomes in the GnomAD database, including 6,838 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 2374 hom., cov: 32)

Exomes 𝑓: 0.063 ( 4464 hom. )

Consequence

PCSK9
NM_174936.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.44

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 1-55052487-C-A is Benign according to our data. Variant chr1-55052487-C-A is described in ClinVar as [Benign]. Clinvar id is 265924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55052487-C-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.657+76C>A		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 link	c.657+76C>A		intron_variant		1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.132

AC:

19845

AN:

150198

Hom.:

2365

Cov.:

show subpopulations

Gnomad AFR

AF:

0.322

Gnomad AMI

AF:

0.0442

Gnomad AMR

AF:

0.0697

Gnomad ASJ

AF:

0.129

Gnomad EAS

AF:

0.0315

Gnomad SAS

AF:

0.0665

Gnomad FIN

AF:

0.0377

Gnomad MID

AF:

0.174

Gnomad NFE

AF:

0.0569

Gnomad OTH

AF:

0.128

GnomAD4 exome

AF:

0.0630

AC:

91709

AN:

1456318

Hom.:

4464

Cov.:

AF XY:

0.0623

AC XY:

45123

AN XY:

724344

show subpopulations

Gnomad4 AFR exome

AF:

0.330

Gnomad4 AMR exome

AF:

0.0499

Gnomad4 ASJ exome

AF:

0.134

Gnomad4 EAS exome

AF:

0.0265

Gnomad4 SAS exome

AF:

0.0628

Gnomad4 FIN exome

AF:

0.0421

Gnomad4 NFE exome

AF:

0.0547

Gnomad4 OTH exome

AF:

0.0796

GnomAD4 genome

AF:

0.132

AC:

19888

AN:

150318

Hom.:

2374

Cov.:

AF XY:

0.128

AC XY:

9375

AN XY:

73280

show subpopulations

Gnomad4 AFR

AF:

0.323

Gnomad4 AMR

AF:

0.0696

Gnomad4 ASJ

AF:

0.129

Gnomad4 EAS

AF:

0.0314

Gnomad4 SAS

AF:

0.0662

Gnomad4 FIN

AF:

0.0377

Gnomad4 NFE

AF:

0.0569

Gnomad4 OTH

AF:

0.128

Alfa

AF:

0.0475

Hom.:

Bravo

AF:

0.141

Asia WGS

AF:

0.0870

AC:

302

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.089

DANN

Benign

0.73

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