rs11144782

Positions:

• chr9-76180297-C-G

Variant summary

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

The NM_001372043.1(PCSK5):​c.2003+599C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 151,932 control chromosomes in the GnomAD database, including 2,340 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 0.16 (2340 hom., cov: 30)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.298

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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK5	NM_001372043.1	c.2003+599C>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.2003+599C>G		intron_variant			NM_001372043.1	ENSP00000500971	A2
PCSK5	ENST00000376752.9	c.2003+599C>G		intron_variant		1		ENSP00000365943
PCSK5	ENST00000424854.6	c.1022+599C>G		intron_variant		5		ENSP00000411654
PCSK5	ENST00000545128.5	c.2003+599C>G		intron_variant		5		ENSP00000446280	P4

Frequencies

GnomAD3 genomes AF: 0.158 AC: 23926 AN: 151814 Hom.: 2341 Cov.: 30

Gnomad AFR AF: 0.0602

Gnomad AMI AF: 0.371

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.377

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.112

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.168

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.157 AC: 23927 AN: 151932 Hom.: 2340 Cov.: 30 AF XY: 0.161 AC XY: 11941 AN XY: 74210

Gnomad4 AFR AF: 0.0600

Gnomad4 AMR AF: 0.204

Gnomad4 ASJ AF: 0.119

Gnomad4 EAS AF: 0.376

Gnomad4 SAS AF: 0.230

Gnomad4 FIN AF: 0.194

Gnomad4 NFE AF: 0.178

Gnomad4 OTH AF: 0.169

Alfa AF: 0.178 Hom.: 340

Bravo AF: 0.155

Asia WGS AF: 0.315 AC: 1094 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.4
DANN	Benign	0.54

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: rs11144782; hg19: chr9-78795213;