chr9-76188596-C-T

Position:

• chr9-76188596-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

PCSK5 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
PCSK5	NM_001372043.1	c.2301C>T	p.Cys767Cys	synonymous_variant	18/38	ENST00000674117.1	NP_001358972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK5	ENST00000674117.1	c.2301C>T	p.Cys767Cys	synonymous_variant	18/38		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

GnomAD3 exomes AF: 0.144 AC: 36165 AN: 251096 Hom.: 3078 AF XY: 0.147 AC XY: 19986 AN XY: 135690

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 SAS exome AF: 0.0939

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

Gnomad4 AFR exome AF: 0.0859

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.199

Gnomad4 EAS exome AF: 0.000680

Gnomad4 SAS exome AF: 0.0954

Gnomad4 FIN exome AF: 0.176

Gnomad4 NFE exome AF: 0.195

Gnomad4 OTH exome AF: 0.167

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

Gnomad4 AFR AF: 0.0892

Gnomad4 AMR AF: 0.151

Gnomad4 ASJ AF: 0.192

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0949

Gnomad4 FIN AF: 0.185

Gnomad4 NFE AF: 0.184

Gnomad4 OTH AF: 0.170

Alfa AF: 0.180 Hom.: 3162

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

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: rs10521468; hg19: chr9-78803512; COSMIC: COSV105310757; COSMIC: COSV105310757;