dbSNP rs7552350: PCSK9:c.657+114C>A (chr1-55052525-C-A) – ACMG Classification: Benign (-20 pts)

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+114C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,535,416 control chromosomes in the GnomAD database, including 19,261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2147 hom., cov: 34)

Exomes 𝑓: 0.16 ( 17114 hom. )

Consequence

PCSK9
NM_174936.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.00500

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 1-55052525-C-A is Benign according to our data. Variant chr1-55052525-C-A is described in ClinVar as [Benign]. Clinvar id is 265929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55052525-C-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.657+114C>A		intron_variant	Intron 4 of 11	ENST00000302118.5	NP_777596.2	Q8NBP7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5 link	c.657+114C>A		intron_variant	Intron 4 of 11	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.163

AC:

24575

AN:

150374

Hom.:

2142

Cov.:

show subpopulations

Gnomad AFR

AF:

0.203

Gnomad AMI

AF:

0.309

Gnomad AMR

AF:

0.143

Gnomad ASJ

AF:

0.175

Gnomad EAS

AF:

0.0496

Gnomad SAS

AF:

0.108

Gnomad FIN

AF:

0.0880

Gnomad MID

AF:

0.148

Gnomad NFE

AF:

0.165

Gnomad OTH

AF:

0.171

GnomAD4 exome

AF:

0.157

AC:

217594

AN:

1384924

Hom.:

17114

Cov.:

AF XY:

0.157

AC XY:

107935

AN XY:

688098

show subpopulations

Gnomad4 AFR exome

AF:

0.214

Gnomad4 AMR exome

AF:

0.103

Gnomad4 ASJ exome

AF:

0.183

Gnomad4 EAS exome

AF:

0.0400

Gnomad4 SAS exome

AF:

0.121

Gnomad4 FIN exome

AF:

0.0922

Gnomad4 NFE exome

AF:

0.167

Gnomad4 OTH exome

AF:

0.153

GnomAD4 genome

AF:

0.163

AC:

24599

AN:

150492

Hom.:

2147

Cov.:

AF XY:

0.157

AC XY:

11539

AN XY:

73358

show subpopulations

Gnomad4 AFR

AF:

0.204

Gnomad4 AMR

AF:

0.142

Gnomad4 ASJ

AF:

0.175

Gnomad4 EAS

AF:

0.0497

Gnomad4 SAS

AF:

0.107

Gnomad4 FIN

AF:

0.0880

Gnomad4 NFE

AF:

0.165

Gnomad4 OTH

AF:

0.169

Alfa

AF:

0.161

Hom.:

264

Bravo

AF:

0.168

Asia WGS

AF:

0.0860

AC:

300

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

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

4.2

DANN

Benign

0.78

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