rs2297342

Variant names:

• chr9-76159037-G-A
• rs2297342
• NM_001372043.1:c.1485G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001372043.1(PCSK5):​c.1485G>A​(p.Ser495Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 1,613,712 control chromosomes in the GnomAD database, including 52,619 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 0.23 (4445 hom., cov: 32)
  • Exomes 𝑓: 0.25 (48174 hom.)
• Consequence: PCSK5 NM_001372043.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.31
• Publications: 16 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP7: Synonymous conserved (PhyloP=-2.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK5	NM_001372043.1	c.1485G>A	p.Ser495Ser	synonymous_variant	Exon 12 of 38	ENST00000674117.1	NP_001358972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK5	ENST00000674117.1	c.1485G>A	p.Ser495Ser	synonymous_variant	Exon 12 of 38		NM_001372043.1	ENSP00000500971.1

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35566 AN: 151924 Hom.: 4435 Cov.: 32

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.253

GnomAD2 exomes AF: 0.268 AC: 67291 AN: 251160 AF XY: 0.263

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.450

Gnomad ASJ exome AF: 0.150

Gnomad EAS exome AF: 0.324

Gnomad FIN exome AF: 0.197

Gnomad NFE exome AF: 0.234

Gnomad OTH exome AF: 0.254

GnomAD4 exome AF: 0.251 AC: 367232 AN: 1461670 Hom.: 48174 Cov.: 34 AF XY: 0.251 AC XY: 182568 AN XY: 727148

African (AFR) AF: 0.180 AC: 6015 AN: 33476

American (AMR) AF: 0.431 AC: 19256 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 4041 AN: 26134

East Asian (EAS) AF: 0.359 AC: 14236 AN: 39698

South Asian (SAS) AF: 0.293 AC: 25280 AN: 86244

European-Finnish (FIN) AF: 0.194 AC: 10386 AN: 53420

Middle Eastern (MID) AF: 0.257 AC: 1482 AN: 5766

European-Non Finnish (NFE) AF: 0.244 AC: 271581 AN: 1111822

Other (OTH) AF: 0.248 AC: 14955 AN: 60386

GnomAD4 genome AF: 0.234 AC: 35590 AN: 152042 Hom.: 4445 Cov.: 32 AF XY: 0.236 AC XY: 17514 AN XY: 74350

African (AFR) AF: 0.185 AC: 7656 AN: 41464

American (AMR) AF: 0.329 AC: 5027 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 570 AN: 3468

East Asian (EAS) AF: 0.324 AC: 1677 AN: 5176

South Asian (SAS) AF: 0.309 AC: 1487 AN: 4818

European-Finnish (FIN) AF: 0.207 AC: 2192 AN: 10584

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.238 AC: 16155 AN: 67958

Other (OTH) AF: 0.251 AC: 529 AN: 2110

Alfa AF: 0.238 Hom.: 18676

Bravo AF: 0.242

Asia WGS AF: 0.332 AC: 1154 AN: 3478

EpiCase AF: 0.236

EpiControl AF: 0.223

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.3
DANN	Benign	0.71
PhyloP100		-2.3
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: rs2297342; hg19: chr9-78773953; COSMIC: COSV65083823;