9-76138408-C-T

Variant names:

• chr9-76138408-C-T
• rs1339246
• NM_001372043.1:c.1312+4196C>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.1312+4196C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 152,034 control chromosomes in the GnomAD database, including 57,819 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 0.87 (57819 hom., cov: 31)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.191
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 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.1312+4196C>T		intron	N/A	NP_001358972.1
	PCSK5	NM_001190482.2		c.1312+4196C>T		intron	N/A	NP_001177411.1
	PCSK5	NM_006200.6		c.1312+4196C>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.1312+4196C>T		intron	N/A	ENSP00000500971.1
	PCSK5	ENST00000376752.9	TSL:1	c.1312+4196C>T		intron	N/A	ENSP00000365943.4
	PCSK5	ENST00000545128.5	TSL:5	c.1312+4196C>T		intron	N/A	ENSP00000446280.1

Frequencies

GnomAD3 genomes AF: 0.871 AC: 132304 AN: 151916 Hom.: 57773 Cov.: 31

Gnomad AFR AF: 0.926

Gnomad AMI AF: 0.821

Gnomad AMR AF: 0.880

Gnomad ASJ AF: 0.820

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.869

Gnomad FIN AF: 0.883

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.827

Gnomad OTH AF: 0.866

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

GnomAD4 genome AF: 0.871 AC: 132412 AN: 152034 Hom.: 57819 Cov.: 31 AF XY: 0.875 AC XY: 65031 AN XY: 74328

African (AFR) AF: 0.926 AC: 38438 AN: 41500

American (AMR) AF: 0.880 AC: 13405 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.820 AC: 2843 AN: 3466

East Asian (EAS) AF: 0.997 AC: 5137 AN: 5152

South Asian (SAS) AF: 0.870 AC: 4188 AN: 4814

European-Finnish (FIN) AF: 0.883 AC: 9351 AN: 10594

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.827 AC: 56209 AN: 67952

Other (OTH) AF: 0.867 AC: 1832 AN: 2112

Alfa AF: 0.836 Hom.: 26465

Bravo AF: 0.875

Asia WGS AF: 0.940 AC: 3269 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.2
DANN	Benign	0.41
PhyloP100		-0.19
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: rs1339246; hg19: chr9-78753324;