9-75941179-C-T

Variant names:

• chr9-75941179-C-T
• rs11144690
• NM_001372043.1:c.297+8696C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001372043.1(PCSK5):​c.297+8696C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0671 in 152,138 control chromosomes in the GnomAD database, including 455 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 0.067 (455 hom., cov: 33)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.747
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372043.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK5	NM_001372043.1	MANE Select	c.297+8696C>T		intron	N/A	NP_001358972.1
	PCSK5	NM_001190482.2		c.297+8696C>T		intron	N/A	NP_001177411.1
	PCSK5	NM_006200.6		c.297+8696C>T		intron	N/A	NP_006191.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK5	ENST00000674117.1	MANE Select	c.297+8696C>T		intron	N/A	ENSP00000500971.1
	PCSK5	ENST00000376752.9	TSL:1	c.297+8696C>T		intron	N/A	ENSP00000365943.4
	PCSK5	ENST00000854198.1		c.297+8696C>T		intron	N/A	ENSP00000524257.1

Frequencies

GnomAD3 genomes AF: 0.0670 AC: 10188 AN: 152020 Hom.: 445 Cov.: 33

Gnomad AFR AF: 0.0679

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.0802

Gnomad ASJ AF: 0.0519

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.0757

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0456

Gnomad OTH AF: 0.0664

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

GnomAD4 genome AF: 0.0671 AC: 10202 AN: 152138 Hom.: 455 Cov.: 33 AF XY: 0.0711 AC XY: 5285 AN XY: 74372

African (AFR) AF: 0.0679 AC: 2817 AN: 41516

American (AMR) AF: 0.0802 AC: 1227 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0519 AC: 180 AN: 3468

East Asian (EAS) AF: 0.239 AC: 1235 AN: 5158

South Asian (SAS) AF: 0.128 AC: 613 AN: 4806

European-Finnish (FIN) AF: 0.0757 AC: 801 AN: 10584

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0456 AC: 3101 AN: 67996

Other (OTH) AF: 0.0743 AC: 157 AN: 2114

Alfa AF: 0.0551 Hom.: 787

Bravo AF: 0.0673

Asia WGS AF: 0.178 AC: 617 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.5
DANN	Benign	0.84
PhyloP100		-0.75
Mutation Taster		=100/0	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: rs11144690; hg19: chr9-78556095;