NM_001372043.1:c.2627-1018G>T

Variant names:

• chr9-76226485-G-T
• rs10746997
• NM_001372043.1:c.2627-1018G>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.2627-1018G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.679 in 151,948 control chromosomes in the GnomAD database, including 35,752 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 0.68 (35752 hom., cov: 30)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.986
• Publications: 6 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]

PCSK5 Gene-Disease associations (from GenCC):

• syndromic congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.792 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK5	NM_001372043.1	MANE Select	c.2627-1018G>T		intron	N/A	NP_001358972.1	A0A669KA35
	PCSK5	NM_001190482.2		c.2627-1018G>T		intron	N/A	NP_001177411.1	Q92824-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK5	ENST00000674117.1	MANE Select	c.2627-1018G>T		intron	N/A	ENSP00000500971.1	A0A669KA35
	PCSK5	ENST00000854198.1		c.2627-1018G>T		intron	N/A	ENSP00000524257.1
	PCSK5	ENST00000545128.5	TSL:5	c.2627-1018G>T		intron	N/A	ENSP00000446280.1	Q92824-1

Frequencies

GnomAD3 genomes AF: 0.679 AC: 103031 AN: 151830 Hom.: 35705 Cov.: 30

Gnomad AFR AF: 0.799

Gnomad AMI AF: 0.568

Gnomad AMR AF: 0.602

Gnomad ASJ AF: 0.639

Gnomad EAS AF: 0.344

Gnomad SAS AF: 0.665

Gnomad FIN AF: 0.617

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.663

Gnomad OTH AF: 0.649

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

GnomAD4 genome AF: 0.679 AC: 103137 AN: 151948 Hom.: 35752 Cov.: 30 AF XY: 0.674 AC XY: 50021 AN XY: 74258

African (AFR) AF: 0.799 AC: 33118 AN: 41450

American (AMR) AF: 0.602 AC: 9189 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.639 AC: 2216 AN: 3468

East Asian (EAS) AF: 0.343 AC: 1765 AN: 5148

South Asian (SAS) AF: 0.664 AC: 3194 AN: 4810

European-Finnish (FIN) AF: 0.617 AC: 6505 AN: 10548

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.663 AC: 45061 AN: 67944

Other (OTH) AF: 0.653 AC: 1378 AN: 2110

Alfa AF: 0.663 Hom.: 61910

Bravo AF: 0.679

Asia WGS AF: 0.529 AC: 1839 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.30
DANN	Benign	0.74
PhyloP100		-0.99
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: rs10746997; hg19: chr9-78841401; COSMIC: COSV70448384;