rs7040769

Positions:

• chr9-75891271-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001372043.1(PCSK5):​c.90T>C​(p.Cys30=) 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

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

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK5	NM_001372043.1	c.90T>C	p.Cys30=	synonymous_variant	1/38	ENST00000674117.1	NP_001358972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK5	ENST00000674117.1	c.90T>C	p.Cys30=	synonymous_variant	1/38		NM_001372043.1	ENSP00000500971	A2
PCSK5	ENST00000376752.9	c.90T>C	p.Cys30=	synonymous_variant	1/21	1		ENSP00000365943
PCSK5	ENST00000545128.5	c.90T>C	p.Cys30=	synonymous_variant	1/37	5		ENSP00000446280	P4
PCSK5	ENST00000376767.7	n.602T>C		non_coding_transcript_exon_variant	1/14	2

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

GnomAD3 exomes AF: 0.147 AC: 25494 AN: 173628 Hom.: 2781 AF XY: 0.141 AC XY: 13640 AN XY: 96594

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 SAS exome AF: 0.0695

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

Gnomad4 AFR exome AF: 0.503

Gnomad4 AMR exome AF: 0.0936

Gnomad4 ASJ exome AF: 0.160

Gnomad4 EAS exome AF: 0.000153

Gnomad4 SAS exome AF: 0.0735

Gnomad4 FIN exome AF: 0.182

Gnomad4 NFE exome AF: 0.136

Gnomad4 OTH exome AF: 0.152

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

Gnomad4 AFR AF: 0.483

Gnomad4 AMR AF: 0.157

Gnomad4 ASJ AF: 0.160

Gnomad4 EAS AF: 0.00137

Gnomad4 SAS AF: 0.0585

Gnomad4 FIN AF: 0.190

Gnomad4 NFE AF: 0.139

Gnomad4 OTH AF: 0.210

Alfa AF: 0.161 Hom.: 3524

Bravo AF: 0.243

Asia WGS AF: 0.0610 AC: 214 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	14
DANN	Benign	0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs7040769; hg19: chr9-78506187;