9-76020120-C-G

Variant names:

• chr9-76020120-C-G
• rs4745488
• NM_001372043.1:c.412-3618C>G

Variant summary

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

The NM_001372043.1(PCSK5):​c.412-3618C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 152,170 control chromosomes in the GnomAD database, including 39,313 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 0.71 (39313 hom., cov: 33)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.175
• 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]

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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.828 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.412-3618C>G		intron	N/A	NP_001358972.1	A0A669KA35
	PCSK5	NM_001190482.2		c.412-3618C>G		intron	N/A	NP_001177411.1	Q92824-1
	PCSK5	NM_006200.6		c.412-3618C>G		intron	N/A	NP_006191.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK5	ENST00000674117.1	MANE Select	c.412-3618C>G		intron	N/A	ENSP00000500971.1	A0A669KA35
	PCSK5	ENST00000376752.9	TSL:1	c.412-3618C>G		intron	N/A	ENSP00000365943.4	Q92824-2
	PCSK5	ENST00000854198.1		c.412-3618C>G		intron	N/A	ENSP00000524257.1

Frequencies

GnomAD3 genomes AF: 0.710 AC: 107975 AN: 152052 Hom.: 39260 Cov.: 33

Gnomad AFR AF: 0.835

Gnomad AMI AF: 0.709

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.375

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.681

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.705

Gnomad OTH AF: 0.695

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

GnomAD4 genome AF: 0.710 AC: 108086 AN: 152170 Hom.: 39313 Cov.: 33 AF XY: 0.704 AC XY: 52327 AN XY: 74378

African (AFR) AF: 0.836 AC: 34713 AN: 41542

American (AMR) AF: 0.565 AC: 8632 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.673 AC: 2335 AN: 3470

East Asian (EAS) AF: 0.376 AC: 1941 AN: 5168

South Asian (SAS) AF: 0.625 AC: 3009 AN: 4818

European-Finnish (FIN) AF: 0.681 AC: 7212 AN: 10588

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.705 AC: 47906 AN: 67984

Other (OTH) AF: 0.693 AC: 1460 AN: 2106

Alfa AF: 0.719 Hom.: 4945

Bravo AF: 0.705

Asia WGS AF: 0.545 AC: 1898 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.5
DANN	Benign	0.39
PhyloP100		-0.17
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: rs4745488; hg19: chr9-78635036;