rs10521468

Variant names:

• chr9-76188596-C-T
• rs10521468
• NM_001372043.1:c.2301C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_001372043.1(PCSK5):​c.2301C>T​(p.Cys767Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,610,410 control chromosomes in the GnomAD database, including 26,664 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 (1840 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24824 hom.)
• Consequence: PCSK5 NM_001372043.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.868
• Publications: 11 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP7: Synonymous conserved (PhyloP=0.868 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK5	NM_001372043.1	c.2301C>T	p.Cys767Cys	synonymous_variant	Exon 18 of 38	ENST00000674117.1	NP_001358972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK5	ENST00000674117.1	c.2301C>T	p.Cys767Cys	synonymous_variant	Exon 18 of 38		NM_001372043.1	ENSP00000500971.1

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22070 AN: 151980 Hom.: 1837 Cov.: 32

Gnomad AFR AF: 0.0890

Gnomad AMI AF: 0.0705

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0944

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.172

GnomAD2 exomes AF: 0.144 AC: 36165 AN: 251096 AF XY: 0.147

Gnomad AFR exome AF: 0.0866

Gnomad AMR exome AF: 0.105

Gnomad ASJ exome AF: 0.202

Gnomad EAS exome AF: 0.000653

Gnomad FIN exome AF: 0.183

Gnomad NFE exome AF: 0.187

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.176 AC: 257299 AN: 1458312 Hom.: 24824 Cov.: 31 AF XY: 0.174 AC XY: 126569 AN XY: 725678

African (AFR) AF: 0.0859 AC: 2872 AN: 33424

American (AMR) AF: 0.108 AC: 4849 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 5206 AN: 26108

East Asian (EAS) AF: 0.000680 AC: 27 AN: 39684

South Asian (SAS) AF: 0.0954 AC: 8224 AN: 86194

European-Finnish (FIN) AF: 0.176 AC: 9403 AN: 53408

Middle Eastern (MID) AF: 0.173 AC: 996 AN: 5758

European-Non Finnish (NFE) AF: 0.195 AC: 215655 AN: 1108756

Other (OTH) AF: 0.167 AC: 10067 AN: 60276

GnomAD4 genome AF: 0.145 AC: 22082 AN: 152098 Hom.: 1840 Cov.: 32 AF XY: 0.144 AC XY: 10687 AN XY: 74340

African (AFR) AF: 0.0892 AC: 3703 AN: 41502

American (AMR) AF: 0.151 AC: 2301 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 666 AN: 3468

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5174

South Asian (SAS) AF: 0.0949 AC: 457 AN: 4816

European-Finnish (FIN) AF: 0.185 AC: 1958 AN: 10570

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.184 AC: 12513 AN: 67978

Other (OTH) AF: 0.170 AC: 358 AN: 2112

Alfa AF: 0.176 Hom.: 3749

Bravo AF: 0.140

Asia WGS AF: 0.0460 AC: 161 AN: 3478

EpiCase AF: 0.192

EpiControl AF: 0.196

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.4
DANN	Benign	0.69
PhyloP100		0.87
PromoterAI		0.0051	Neutral
Mutation Taster		=92/8	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: rs10521468; hg19: chr9-78803512; COSMIC: COSV105310757; COSMIC: COSV105310757;