chr1-55047848-C-G

Variant names:

• chr1-55047848-C-G
• rs529787
• NM_174936.4:c.523+1202C>G

Variant summary

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

The NM_001407240.1(PCSK9):​c.646+1202C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 152,136 control chromosomes in the GnomAD database, including 2,015 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 0.15 (2015 hom., cov: 32)
• Consequence: PCSK9 NM_001407240.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.539
• Publications: 7 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407240.1. 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.523+1202C>G		intron	N/A	NP_777596.2
	PCSK9	NM_001407240.1		c.646+1202C>G		intron	N/A	NP_001394169.1
	PCSK9	NM_001407241.1		c.523+1202C>G		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.523+1202C>G		intron	N/A	ENSP00000303208.5
	PCSK9	ENST00000710286.1		c.880+1202C>G		intron	N/A	ENSP00000518176.1
	PCSK9	ENST00000713786.1		c.646+1202C>G		intron	N/A	ENSP00000519088.1

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22289 AN: 152018 Hom.: 2014 Cov.: 32

Gnomad AFR AF: 0.0661

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.171

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

GnomAD4 genome AF: 0.147 AC: 22294 AN: 152136 Hom.: 2015 Cov.: 32 AF XY: 0.144 AC XY: 10733 AN XY: 74368

African (AFR) AF: 0.0660 AC: 2741 AN: 41508

American (AMR) AF: 0.149 AC: 2284 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 606 AN: 3470

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5168

South Asian (SAS) AF: 0.139 AC: 667 AN: 4814

European-Finnish (FIN) AF: 0.150 AC: 1591 AN: 10596

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13812 AN: 67970

Other (OTH) AF: 0.168 AC: 355 AN: 2112

Alfa AF: 0.113 Hom.: 211

Bravo AF: 0.142

Asia WGS AF: 0.0610 AC: 213 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.1
DANN	Benign	0.64
PhyloP100		0.54
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: rs529787; hg19: chr1-55513521;