rs2261722

Variant names:

• chr9-76254665-G-A
• rs2261722
• NM_001372043.1:c.3142+13981G>A

Variant summary

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

The ENST00000674117.1(PCSK5):​c.3142+13981G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 152,002 control chromosomes in the GnomAD database, including 7,281 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 0.31 (7281 hom., cov: 32)
• Consequence: PCSK5 ENST00000674117.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.692
• Publications: 4 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000674117.1. 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.3142+13981G>A		intron	N/A	NP_001358972.1
	PCSK5	NM_001190482.2		c.3142+13981G>A		intron	N/A	NP_001177411.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK5	ENST00000674117.1	MANE Select	c.3142+13981G>A		intron	N/A	ENSP00000500971.1
	PCSK5	ENST00000545128.5	TSL:5	c.3142+13981G>A		intron	N/A	ENSP00000446280.1
	PCSK5	ENST00000424854.6	TSL:5	c.2161+13981G>A		intron	N/A	ENSP00000411654.1

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46539 AN: 151884 Hom.: 7276 Cov.: 32

Gnomad AFR AF: 0.283

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.398

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.362

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

GnomAD4 genome AF: 0.306 AC: 46575 AN: 152002 Hom.: 7281 Cov.: 32 AF XY: 0.306 AC XY: 22777 AN XY: 74318

African (AFR) AF: 0.283 AC: 11725 AN: 41452

American (AMR) AF: 0.399 AC: 6085 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 1464 AN: 3470

East Asian (EAS) AF: 0.317 AC: 1638 AN: 5164

South Asian (SAS) AF: 0.390 AC: 1875 AN: 4812

European-Finnish (FIN) AF: 0.227 AC: 2401 AN: 10574

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.298 AC: 20282 AN: 67948

Other (OTH) AF: 0.361 AC: 762 AN: 2112

Alfa AF: 0.308 Hom.: 31609

Bravo AF: 0.316

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.80
PhyloP100		-0.69
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2261722; hg19: chr9-78869581;