9-75891265-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_001372043.1(PCSK5):c.84C>A(p.Pro28=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,530,176 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0095 (21 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (34 hom.)
• Consequence: PCSK5 NM_001372043.1 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.15

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 9-75891265-C-A is Benign according to our data. Variant chr9-75891265-C-A is described in ClinVar as [Benign]. Clinvar id is 716920.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0095 (1445/152178) while in subpopulation AFR AF= 0.0308 (1280/41540). AF 95% confidence interval is 0.0294. There are 21 homozygotes in gnomad4. There are 720 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK5	NM_001372043.1	c.84C>A	p.Pro28=	synonymous_variant	1/38	ENST00000674117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK5	ENST00000674117.1	c.84C>A	p.Pro28=	synonymous_variant	1/38		NM_001372043.1	A2
PCSK5	ENST00000376752.9	c.84C>A	p.Pro28=	synonymous_variant	1/21	1
PCSK5	ENST00000545128.5	c.84C>A	p.Pro28=	synonymous_variant	1/37	5		P4
PCSK5	ENST00000376767.7	n.596C>A		non_coding_transcript_exon_variant	1/14	2

Frequencies

GnomAD3 genomes AF: 0.00945 AC: 1437 AN: 152060 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.0307

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00816

GnomAD3 exomes AF: 0.00274 AC: 477 AN: 174144 Hom.: 7 AF XY: 0.00216 AC XY: 209 AN XY: 96786

Gnomad AFR exome AF: 0.0313

Gnomad AMR exome AF: 0.00306

Gnomad ASJ exome AF: 0.000999

Gnomad EAS exome AF: 0.000107

Gnomad SAS exome AF: 0.0000488

Gnomad FIN exome AF: 0.000245

Gnomad NFE exome AF: 0.000815

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00131 AC: 1809 AN: 1377998 Hom.: 34 Cov.: 31 AF XY: 0.00123 AC XY: 840 AN XY: 683928

Gnomad4 AFR exome AF: 0.0332

Gnomad4 AMR exome AF: 0.00394

Gnomad4 ASJ exome AF: 0.000816

Gnomad4 EAS exome AF: 0.0000305

Gnomad4 SAS exome AF: 0.000122

Gnomad4 FIN exome AF: 0.000211

Gnomad4 NFE exome AF: 0.000514

Gnomad4 OTH exome AF: 0.00308

GnomAD4 genome AF: 0.00950 AC: 1445 AN: 152178 Hom.: 21 Cov.: 33 AF XY: 0.00968 AC XY: 720 AN XY: 74406

Gnomad4 AFR AF: 0.0308

Gnomad4 AMR AF: 0.00581

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.00807

Alfa AF: 0.00491 Hom.: 4

Bravo AF: 0.0111

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 19, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	3.3
Dann	Benign	0.93

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: rs34813806; hg19: chr9-78506181;