rs7020560

Variant names:

• chr9-75891229-G-A
• rs7020560
• NM_001372043.1:c.48G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001372043.1(PCSK5):​c.48G>A​(p.Leu16Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0748 in 1,518,016 control chromosomes in the GnomAD database, including 6,709 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 0.13 (2348 hom., cov: 33)
  • Exomes 𝑓: 0.069 (4361 hom.)
• Consequence: PCSK5 NM_001372043.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.855
• Publications: 4 publications found

Genes affected

PCSK5 (HGNC:8747): (proprotein convertase subtilisin/kexin type 5) 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 initial autocatalytic processing event in the ER to generate a heterodimer which exits the ER. It then sorts to the trans-Golgi network where a second autocatalytic event takes place and the catalytic activity is acquired. This encoded protein is widely expressed and one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. It mediates posttranslational endoproteolytic processing for several integrin alpha subunits and is thought to process prorenin, pro-membrane type-1 matrix metalloproteinase and HIV-1 glycoprotein gp160. Alternative splicing results in multiple transcript variants, some of which encode distinct isoforms, including a protease packaged into dense core granules (PC5A) and a type 1 membrane bound protease (PC5B). [provided by RefSeq, May 2014]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP7: Synonymous conserved (PhyloP=0.855 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372043.1. 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
	PCSK5	NM_001372043.1	MANE Select	c.48G>A	p.Leu16Leu	synonymous	Exon 1 of 38	NP_001358972.1
	PCSK5	NM_001190482.2		c.48G>A	p.Leu16Leu	synonymous	Exon 1 of 37	NP_001177411.1
	PCSK5	NM_006200.6		c.48G>A	p.Leu16Leu	synonymous	Exon 1 of 21	NP_006191.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK5	ENST00000674117.1	MANE Select	c.48G>A	p.Leu16Leu	synonymous	Exon 1 of 38	ENSP00000500971.1
	PCSK5	ENST00000376752.9	TSL:1	c.48G>A	p.Leu16Leu	synonymous	Exon 1 of 21	ENSP00000365943.4
	PCSK5	ENST00000545128.5	TSL:5	c.48G>A	p.Leu16Leu	synonymous	Exon 1 of 37	ENSP00000446280.1

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19875 AN: 152072 Hom.: 2345 Cov.: 33

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0703

Gnomad ASJ AF: 0.0470

Gnomad EAS AF: 0.000776

Gnomad SAS AF: 0.0219

Gnomad FIN AF: 0.0908

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.0651

Gnomad OTH AF: 0.114

GnomAD2 exomes AF: 0.0713 AC: 11845 AN: 166054 AF XY: 0.0658

Gnomad AFR exome AF: 0.307

Gnomad AMR exome AF: 0.0358

Gnomad ASJ exome AF: 0.0525

Gnomad EAS exome AF: 0.000113

Gnomad FIN exome AF: 0.0882

Gnomad NFE exome AF: 0.0652

Gnomad OTH exome AF: 0.0726

GnomAD4 exome AF: 0.0686 AC: 93668 AN: 1365826 Hom.: 4361 Cov.: 31 AF XY: 0.0668 AC XY: 45174 AN XY: 676764

African (AFR) AF: 0.320 AC: 8597 AN: 26830

American (AMR) AF: 0.0451 AC: 1057 AN: 23462

Ashkenazi Jewish (ASJ) AF: 0.0512 AC: 1168 AN: 22816

East Asian (EAS) AF: 0.00 AC: 0 AN: 32404

South Asian (SAS) AF: 0.0239 AC: 1708 AN: 71604

European-Finnish (FIN) AF: 0.0849 AC: 4403 AN: 51864

Middle Eastern (MID) AF: 0.0998 AC: 547 AN: 5482

European-Non Finnish (NFE) AF: 0.0670 AC: 72058 AN: 1075110

Other (OTH) AF: 0.0734 AC: 4130 AN: 56254

GnomAD4 genome AF: 0.131 AC: 19886 AN: 152190 Hom.: 2348 Cov.: 33 AF XY: 0.129 AC XY: 9584 AN XY: 74410

African (AFR) AF: 0.309 AC: 12815 AN: 41502

American (AMR) AF: 0.0702 AC: 1074 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0470 AC: 163 AN: 3468

East Asian (EAS) AF: 0.000973 AC: 5 AN: 5140

South Asian (SAS) AF: 0.0217 AC: 105 AN: 4828

European-Finnish (FIN) AF: 0.0908 AC: 964 AN: 10616

Middle Eastern (MID) AF: 0.151 AC: 44 AN: 292

European-Non Finnish (NFE) AF: 0.0651 AC: 4427 AN: 68008

Other (OTH) AF: 0.113 AC: 239 AN: 2114

Alfa AF: 0.0877 Hom.: 723

Bravo AF: 0.138

Asia WGS AF: 0.0270 AC: 95 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
DANN	Benign	0.97
PhyloP100		0.85
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: rs7020560; hg19: chr9-78506145; COSMIC: COSV65097645;