rs7040769

Variant names:

• chr9-75891271-T-C
• rs7040769
• NM_001372043.1:c.90T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001372043.1(PCSK5):​c.90T>C​(p.Cys30Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,529,892 control chromosomes in the GnomAD database, including 22,194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (6069 hom., cov: 32)
  • Exomes 𝑓: 0.14 (16125 hom.)
• Consequence: PCSK5 NM_001372043.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.39
• Publications: 8 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 9-75891271-T-C is Benign according to our data. Variant chr9-75891271-T-C is described in ClinVar as Benign. ClinVar VariationId is 1179816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.477 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.90T>C	p.Cys30Cys	synonymous	Exon 1 of 38	NP_001358972.1
	PCSK5	NM_001190482.2		c.90T>C	p.Cys30Cys	synonymous	Exon 1 of 37	NP_001177411.1
	PCSK5	NM_006200.6		c.90T>C	p.Cys30Cys	synonymous	Exon 1 of 21	NP_006191.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK5	ENST00000674117.1	MANE Select	c.90T>C	p.Cys30Cys	synonymous	Exon 1 of 38	ENSP00000500971.1
	PCSK5	ENST00000376752.9	TSL:1	c.90T>C	p.Cys30Cys	synonymous	Exon 1 of 21	ENSP00000365943.4
	PCSK5	ENST00000545128.5	TSL:5	c.90T>C	p.Cys30Cys	synonymous	Exon 1 of 37	ENSP00000446280.1

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35316 AN: 151874 Hom.: 6063 Cov.: 32

Gnomad AFR AF: 0.483

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.00117

Gnomad SAS AF: 0.0584

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.213

GnomAD2 exomes AF: 0.147 AC: 25494 AN: 173628 AF XY: 0.141

Gnomad AFR exome AF: 0.485

Gnomad AMR exome AF: 0.0790

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.185

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.139 AC: 192026 AN: 1377900 Hom.: 16125 Cov.: 32 AF XY: 0.137 AC XY: 93842 AN XY: 684002

African (AFR) AF: 0.503 AC: 13743 AN: 27332

American (AMR) AF: 0.0936 AC: 2416 AN: 25814

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 3738 AN: 23306

East Asian (EAS) AF: 0.000153 AC: 5 AN: 32720

South Asian (SAS) AF: 0.0735 AC: 5401 AN: 73462

European-Finnish (FIN) AF: 0.182 AC: 9477 AN: 52214

Middle Eastern (MID) AF: 0.227 AC: 1254 AN: 5522

European-Non Finnish (NFE) AF: 0.136 AC: 147345 AN: 1080686

Other (OTH) AF: 0.152 AC: 8647 AN: 56844

GnomAD4 genome AF: 0.233 AC: 35354 AN: 151992 Hom.: 6069 Cov.: 32 AF XY: 0.231 AC XY: 17133 AN XY: 74272

African (AFR) AF: 0.483 AC: 20009 AN: 41456

American (AMR) AF: 0.157 AC: 2399 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 554 AN: 3472

East Asian (EAS) AF: 0.00137 AC: 7 AN: 5124

South Asian (SAS) AF: 0.0585 AC: 281 AN: 4806

European-Finnish (FIN) AF: 0.190 AC: 2013 AN: 10586

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9454 AN: 67930

Other (OTH) AF: 0.210 AC: 444 AN: 2112

Alfa AF: 0.189 Hom.: 7859

Bravo AF: 0.243

Asia WGS AF: 0.0610 AC: 214 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	14
DANN	Benign	0.79
PhyloP100		3.4
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: rs7040769; hg19: chr9-78506187;