rs483462

Positions:

• chr1-55059727-G-A
• chr1-55059727-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_174936.4(PCSK9):​c.1681+64G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.695 in 1,526,076 control chromosomes in the GnomAD database, including 374,065 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (32361 hom., cov: 34)
  • Exomes 𝑓: 0.70 (341704 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.58

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 1-55059727-G-A is Benign according to our data. Variant chr1-55059727-G-A is described in ClinVar as [Benign]. Clinvar id is 265948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55059727-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4	c.1681+64G>A		intron_variant		ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5	c.1681+64G>A		intron_variant		1	NM_174936.4	P2

Frequencies

GnomAD3 genomes AF: 0.634 AC: 96354 AN: 152022 Hom.: 32358 Cov.: 34

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.708

Gnomad AMR AF: 0.775

Gnomad ASJ AF: 0.628

Gnomad EAS AF: 0.859

Gnomad SAS AF: 0.765

Gnomad FIN AF: 0.719

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.702

Gnomad OTH AF: 0.681

GnomAD4 exome AF: 0.702 AC: 965006 AN: 1373936 Hom.: 341704 AF XY: 0.705 AC XY: 476105 AN XY: 675774

Gnomad4 AFR exome AF: 0.380

Gnomad4 AMR exome AF: 0.828

Gnomad4 ASJ exome AF: 0.625

Gnomad4 EAS exome AF: 0.860

Gnomad4 SAS exome AF: 0.753

Gnomad4 FIN exome AF: 0.721

Gnomad4 NFE exome AF: 0.700

Gnomad4 OTH exome AF: 0.689

GnomAD4 genome AF: 0.633 AC: 96377 AN: 152140 Hom.: 32361 Cov.: 34 AF XY: 0.641 AC XY: 47648 AN XY: 74376

Gnomad4 AFR AF: 0.400

Gnomad4 AMR AF: 0.776

Gnomad4 ASJ AF: 0.628

Gnomad4 EAS AF: 0.859

Gnomad4 SAS AF: 0.765

Gnomad4 FIN AF: 0.719

Gnomad4 NFE AF: 0.702

Gnomad4 OTH AF: 0.683

Alfa AF: 0.672 Hom.: 14097

Bravo AF: 0.627

Asia WGS AF: 0.771 AC: 2679 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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	-0.96
CADD	Benign	0.0050
DANN	Benign	0.45
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

Other links and lift over

dbSNP: rs483462; hg19: chr1-55525400;