rs10869726

Positions:

• chr9-76189788-G-A
• chr9-76189788-G-T

Variant summary

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

The NM_001372043.1(PCSK5):​c.2626+42G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,011,794 control chromosomes in the GnomAD database, including 8,646 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 (1970 hom., cov: 32)
  • Exomes 𝑓: 0.12 (6676 hom.)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.399

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=-0.77).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK5	NM_001372043.1	c.2626+42G>A		intron_variant		ENST00000674117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK5	ENST00000674117.1	c.2626+42G>A		intron_variant			NM_001372043.1	A2

Frequencies

GnomAD3 genomes AF: 0.153 AC: 22645 AN: 147924 Hom.: 1967 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.0949

Gnomad AMR AF: 0.0957

Gnomad ASJ AF: 0.0899

Gnomad EAS AF: 0.0825

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.145

GnomAD3 exomes AF: 0.127 AC: 26136 AN: 205320 Hom.: 1700 AF XY: 0.127 AC XY: 13943 AN XY: 109616

Gnomad AFR exome AF: 0.251

Gnomad AMR exome AF: 0.0731

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.0854

Gnomad SAS exome AF: 0.106

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.120 AC: 103249 AN: 863752 Hom.: 6676 Cov.: 12 AF XY: 0.120 AC XY: 54036 AN XY: 451588

Gnomad4 AFR exome AF: 0.252

Gnomad4 AMR exome AF: 0.0722

Gnomad4 ASJ exome AF: 0.0884

Gnomad4 EAS exome AF: 0.0953

Gnomad4 SAS exome AF: 0.0962

Gnomad4 FIN exome AF: 0.117

Gnomad4 NFE exome AF: 0.123

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.153 AC: 22674 AN: 148042 Hom.: 1970 Cov.: 32 AF XY: 0.151 AC XY: 10945 AN XY: 72364

Gnomad4 AFR AF: 0.246

Gnomad4 AMR AF: 0.0956

Gnomad4 ASJ AF: 0.0899

Gnomad4 EAS AF: 0.0827

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.127

Gnomad4 OTH AF: 0.149

Alfa AF: 0.120 Hom.: 1442

Bravo AF: 0.153

Asia WGS AF: 0.111 AC: 384 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.4
DANN	Benign	0.80

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: rs10869726; hg19: chr9-78804704; COSMIC: COSV65085552;