rs613855

Positions:

• chr1-55052188-C-G
• chr1-55052188-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_174936.4(PCSK9):​c.524-90C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 1,568,736 control chromosomes in the GnomAD database, including 187,046 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.42 (15237 hom., cov: 31)
  • Exomes 𝑓: 0.48 (171809 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-55052188-C-G is Benign according to our data. Variant chr1-55052188-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.524-90C>G		intron_variant		ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.524-90C>G		intron_variant		1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64302 AN: 151760 Hom.: 15229 Cov.: 31

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.605

Gnomad ASJ AF: 0.440

Gnomad EAS AF: 0.767

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.467

GnomAD4 exome AF: 0.485 AC: 687062 AN: 1416856 Hom.: 171809 Cov.: 25 AF XY: 0.482 AC XY: 340886 AN XY: 707502

Gnomad4 AFR exome AF: 0.218

Gnomad4 AMR exome AF: 0.724

Gnomad4 ASJ exome AF: 0.437

Gnomad4 EAS exome AF: 0.763

Gnomad4 SAS exome AF: 0.454

Gnomad4 FIN exome AF: 0.429

Gnomad4 NFE exome AF: 0.479

Gnomad4 OTH exome AF: 0.488

GnomAD4 genome AF: 0.424 AC: 64339 AN: 151880 Hom.: 15237 Cov.: 31 AF XY: 0.426 AC XY: 31615 AN XY: 74222

Gnomad4 AFR AF: 0.229

Gnomad4 AMR AF: 0.606

Gnomad4 ASJ AF: 0.440

Gnomad4 EAS AF: 0.767

Gnomad4 SAS AF: 0.471

Gnomad4 FIN AF: 0.412

Gnomad4 NFE AF: 0.473

Gnomad4 OTH AF: 0.471

Alfa AF: 0.330 Hom.: 1058

Bravo AF: 0.435

Asia WGS AF: 0.602 AC: 2092 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.79
DANN	Benign	0.60
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: rs613855; hg19: chr1-55517861;