9-76186555-C-G

Variant names:

• chr9-76186555-C-G
• rs4745522
• NM_001372043.1:c.2282+1798C>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.2282+1798C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0972 in 152,170 control chromosomes in the GnomAD database, including 900 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 0.097 (900 hom., cov: 32)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0910
• 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK5	NM_001372043.1	c.2282+1798C>G		intron_variant	Intron 17 of 37	ENST00000674117.1	NP_001358972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK5	ENST00000674117.1	c.2282+1798C>G		intron_variant	Intron 17 of 37		NM_001372043.1	ENSP00000500971.1
PCSK5	ENST00000376752.9	c.2282+1798C>G		intron_variant	Intron 17 of 20	1		ENSP00000365943.4
PCSK5	ENST00000545128.5	c.2282+1798C>G		intron_variant	Intron 17 of 36	5		ENSP00000446280.1
PCSK5	ENST00000424854.6	c.1301+1798C>G		intron_variant	Intron 10 of 30	5		ENSP00000411654.1

Frequencies

GnomAD3 genomes AF: 0.0973 AC: 14792 AN: 152052 Hom.: 898 Cov.: 32

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.0561

Gnomad FIN AF: 0.0930

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.122

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

GnomAD4 genome AF: 0.0972 AC: 14795 AN: 152170 Hom.: 900 Cov.: 32 AF XY: 0.0960 AC XY: 7141 AN XY: 74398

African (AFR) AF: 0.0268 AC: 1115 AN: 41546

American (AMR) AF: 0.149 AC: 2281 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 514 AN: 3472

East Asian (EAS) AF: 0.143 AC: 742 AN: 5178

South Asian (SAS) AF: 0.0570 AC: 275 AN: 4826

European-Finnish (FIN) AF: 0.0930 AC: 984 AN: 10578

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8487 AN: 67976

Other (OTH) AF: 0.122 AC: 258 AN: 2116

Alfa AF: 0.0572 Hom.: 66

Bravo AF: 0.0994

Asia WGS AF: 0.101 AC: 351 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.0
DANN	Benign	0.46
PhyloP100		0.091
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: rs4745522; hg19: chr9-78801471;