rs568052

Variant names:

• chr1-55059169-G-A
• rs568052
• NM_174936.4:c.1504-317G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-55059169-G-A
• chr1-55059169-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_174936.4(PCSK9):​c.1504-317G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 152,118 control chromosomes in the GnomAD database, including 32,378 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.63 (32378 hom., cov: 33)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.577
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, autosomal dominant, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174936.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	NM_174936.4	MANE Select	c.1504-317G>A		intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.1627-317G>A		intron	N/A	NP_001394169.1
	PCSK9	NM_001407241.1		c.1504-275G>A		intron	N/A	NP_001394170.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.1504-317G>A		intron	N/A	ENSP00000303208.5
	PCSK9	ENST00000710286.1		c.1861-317G>A		intron	N/A	ENSP00000518176.1
	PCSK9	ENST00000713786.1		c.1627-317G>A		intron	N/A	ENSP00000519088.1

Frequencies

GnomAD3 genomes AF: 0.634 AC: 96356 AN: 151998 Hom.: 32375 Cov.: 33

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.710

Gnomad AMR AF: 0.775

Gnomad ASJ AF: 0.628

Gnomad EAS AF: 0.861

Gnomad SAS AF: 0.766

Gnomad FIN AF: 0.719

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.702

Gnomad OTH AF: 0.681

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

GnomAD4 genome AF: 0.634 AC: 96379 AN: 152118 Hom.: 32378 Cov.: 33 AF XY: 0.641 AC XY: 47643 AN XY: 74366

African (AFR) AF: 0.399 AC: 16576 AN: 41496

American (AMR) AF: 0.776 AC: 11856 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 2176 AN: 3466

East Asian (EAS) AF: 0.861 AC: 4447 AN: 5162

South Asian (SAS) AF: 0.765 AC: 3695 AN: 4828

European-Finnish (FIN) AF: 0.719 AC: 7608 AN: 10584

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.702 AC: 47747 AN: 67982

Other (OTH) AF: 0.683 AC: 1440 AN: 2108

Alfa AF: 0.673 Hom.: 97369

Bravo AF: 0.627

Asia WGS AF: 0.770 AC: 2677 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.6
DANN	Benign	0.58
PhyloP100		0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs568052; hg19: chr1-55524842; COSMIC: COSV56161316;