rs693668

Positions:

• chr1-55055436-G-A
• chr1-55055436-G-C

Variant summary

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

The NM_174936.4(PCSK9):​c.800-557G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 151,924 control chromosomes in the GnomAD database, including 25,593 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency: Genomes: 𝑓 0.56 (25593 hom., cov: 31)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 1-55055436-G-A is Benign according to our data. Variant chr1-55055436-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.800-557G>A		intron_variant		ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.800-557G>A		intron_variant		1	NM_174936.4	ENSP00000303208	P2

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85552 AN: 151806 Hom.: 25591 Cov.: 31

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.637

Gnomad AMR AF: 0.688

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.761

Gnomad SAS AF: 0.608

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.647

Gnomad OTH AF: 0.602

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.563 AC: 85595 AN: 151924 Hom.: 25593 Cov.: 31 AF XY: 0.565 AC XY: 41989 AN XY: 74272

Gnomad4 AFR AF: 0.348

Gnomad4 AMR AF: 0.688

Gnomad4 ASJ AF: 0.586

Gnomad4 EAS AF: 0.762

Gnomad4 SAS AF: 0.608

Gnomad4 FIN AF: 0.554

Gnomad4 NFE AF: 0.647

Gnomad4 OTH AF: 0.602

Alfa AF: 0.631 Hom.: 38702

Bravo AF: 0.565

Asia WGS AF: 0.657 AC: 2282 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
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: rs693668; hg19: chr1-55521109;