9-76239396-T-G

Variant names:

• chr9-76239396-T-G
• rs2007744
• NM_001372043.1:c.3073+231T>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.3073+231T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.816 in 152,160 control chromosomes in the GnomAD database, including 51,020 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 0.82 (51020 hom., cov: 32)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.669
• Publications: 2 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.966 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.3073+231T>G		intron	N/A	NP_001358972.1
	PCSK5	NM_001190482.2		c.3073+231T>G		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.3073+231T>G		intron	N/A	ENSP00000500971.1
	PCSK5	ENST00000545128.5	TSL:5	c.3073+231T>G		intron	N/A	ENSP00000446280.1
	PCSK5	ENST00000424854.6	TSL:5	c.2092+231T>G		intron	N/A	ENSP00000411654.1

Frequencies

GnomAD3 genomes AF: 0.816 AC: 124116 AN: 152042 Hom.: 50991 Cov.: 32

Gnomad AFR AF: 0.730

Gnomad AMI AF: 0.901

Gnomad AMR AF: 0.811

Gnomad ASJ AF: 0.900

Gnomad EAS AF: 0.989

Gnomad SAS AF: 0.769

Gnomad FIN AF: 0.874

Gnomad MID AF: 0.790

Gnomad NFE AF: 0.846

Gnomad OTH AF: 0.816

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

GnomAD4 genome AF: 0.816 AC: 124195 AN: 152160 Hom.: 51020 Cov.: 32 AF XY: 0.817 AC XY: 60768 AN XY: 74406

African (AFR) AF: 0.730 AC: 30290 AN: 41482

American (AMR) AF: 0.811 AC: 12397 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.900 AC: 3126 AN: 3472

East Asian (EAS) AF: 0.988 AC: 5107 AN: 5168

South Asian (SAS) AF: 0.770 AC: 3712 AN: 4822

European-Finnish (FIN) AF: 0.874 AC: 9273 AN: 10606

Middle Eastern (MID) AF: 0.795 AC: 232 AN: 292

European-Non Finnish (NFE) AF: 0.846 AC: 57512 AN: 68006

Other (OTH) AF: 0.817 AC: 1726 AN: 2112

Alfa AF: 0.832 Hom.: 101607

Bravo AF: 0.810

Asia WGS AF: 0.856 AC: 2979 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.9
DANN	Benign	0.45
PhyloP100		0.67
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: rs2007744; hg19: chr9-78854312;