rs2270570

Positions:

• chr9-76181606-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001372043.1(PCSK5):​c.2197+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 1,576,876 control chromosomes in the GnomAD database, including 37,961 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 0.18 (2862 hom., cov: 32)
  • Exomes 𝑓: 0.22 (35099 hom.)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.384

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK5	NM_001372043.1	c.2197+15A>G		intron_variant		ENST00000674117.1	NP_001358972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK5	ENST00000674117.1	c.2197+15A>G		intron_variant			NM_001372043.1	ENSP00000500971	A2
PCSK5	ENST00000376752.9	c.2197+15A>G		intron_variant		1		ENSP00000365943
PCSK5	ENST00000424854.6	c.1216+15A>G		intron_variant		5		ENSP00000411654
PCSK5	ENST00000545128.5	c.2197+15A>G		intron_variant		5		ENSP00000446280	P4

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27655 AN: 152046 Hom.: 2861 Cov.: 32

Gnomad AFR AF: 0.0986

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.167

GnomAD3 exomes AF: 0.195 AC: 46327 AN: 237402 Hom.: 4988 AF XY: 0.201 AC XY: 25798 AN XY: 128110

Gnomad AFR exome AF: 0.0977

Gnomad AMR exome AF: 0.0952

Gnomad ASJ exome AF: 0.194

Gnomad EAS exome AF: 0.134

Gnomad SAS exome AF: 0.209

Gnomad FIN exome AF: 0.266

Gnomad NFE exome AF: 0.232

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.217 AC: 309641 AN: 1424712 Hom.: 35099 Cov.: 24 AF XY: 0.218 AC XY: 154218 AN XY: 708442

Gnomad4 AFR exome AF: 0.0964

Gnomad4 AMR exome AF: 0.101

Gnomad4 ASJ exome AF: 0.187

Gnomad4 EAS exome AF: 0.139

Gnomad4 SAS exome AF: 0.203

Gnomad4 FIN exome AF: 0.264

Gnomad4 NFE exome AF: 0.229

Gnomad4 OTH exome AF: 0.200

GnomAD4 genome AF: 0.182 AC: 27671 AN: 152164 Hom.: 2862 Cov.: 32 AF XY: 0.181 AC XY: 13470 AN XY: 74384

Gnomad4 AFR AF: 0.0986

Gnomad4 AMR AF: 0.131

Gnomad4 ASJ AF: 0.192

Gnomad4 EAS AF: 0.134

Gnomad4 SAS AF: 0.194

Gnomad4 FIN AF: 0.268

Gnomad4 NFE AF: 0.233

Gnomad4 OTH AF: 0.167

Alfa AF: 0.212 Hom.: 5628

Bravo AF: 0.165

Asia WGS AF: 0.161 AC: 558 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	12
DANN	Benign	0.87

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: rs2270570; hg19: chr9-78796522; COSMIC: COSV65089261;