rs2270570

Variant names:

• chr9-76181606-A-G
• rs2270570
• NM_001372043.1:c.2197+15A>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.2197+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 1,576,876 control chromosomes in the GnomAD database, including 37,961 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 0.18 (2862 hom., cov: 32)
  • Exomes 𝑓: 0.22 (35099 hom.)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.384
• Publications: 9 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]

PCSK5 Gene-Disease associations (from GenCC):

• syndromic congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.23 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK5	NM_001372043.1	MANE Select	c.2197+15A>G		intron	N/A	NP_001358972.1	A0A669KA35
	PCSK5	NM_001190482.2		c.2197+15A>G		intron	N/A	NP_001177411.1	Q92824-1
	PCSK5	NM_006200.6		c.2197+15A>G		intron	N/A	NP_006191.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK5	ENST00000674117.1	MANE Select	c.2197+15A>G		intron	N/A	ENSP00000500971.1	A0A669KA35
	PCSK5	ENST00000376752.9	TSL:1	c.2197+15A>G		intron	N/A	ENSP00000365943.4	Q92824-2
	PCSK5	ENST00000854198.1		c.2197+15A>G		intron	N/A	ENSP00000524257.1

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27655 AN: 152046 Hom.: 2861 Cov.: 32

Gnomad AFR AF: 0.0986

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.167

GnomAD2 exomes AF: 0.195 AC: 46327 AN: 237402 AF XY: 0.201

Gnomad AFR exome AF: 0.0977

Gnomad AMR exome AF: 0.0952

Gnomad ASJ exome AF: 0.194

Gnomad EAS exome AF: 0.134

Gnomad FIN exome AF: 0.266

Gnomad NFE exome AF: 0.232

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.217 AC: 309641 AN: 1424712 Hom.: 35099 Cov.: 24 AF XY: 0.218 AC XY: 154218 AN XY: 708442

African (AFR) AF: 0.0964 AC: 3134 AN: 32514

American (AMR) AF: 0.101 AC: 4315 AN: 42718

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 4673 AN: 25048

East Asian (EAS) AF: 0.139 AC: 5421 AN: 39132

South Asian (SAS) AF: 0.203 AC: 16880 AN: 83322

European-Finnish (FIN) AF: 0.264 AC: 14000 AN: 52994

Middle Eastern (MID) AF: 0.126 AC: 711 AN: 5628

European-Non Finnish (NFE) AF: 0.229 AC: 248718 AN: 1084414

Other (OTH) AF: 0.200 AC: 11789 AN: 58942

GnomAD4 genome AF: 0.182 AC: 27671 AN: 152164 Hom.: 2862 Cov.: 32 AF XY: 0.181 AC XY: 13470 AN XY: 74384

African (AFR) AF: 0.0986 AC: 4098 AN: 41550

American (AMR) AF: 0.131 AC: 1996 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 667 AN: 3468

East Asian (EAS) AF: 0.134 AC: 690 AN: 5158

South Asian (SAS) AF: 0.194 AC: 934 AN: 4824

European-Finnish (FIN) AF: 0.268 AC: 2834 AN: 10590

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.233 AC: 15856 AN: 67970

Other (OTH) AF: 0.167 AC: 352 AN: 2112

Alfa AF: 0.210 Hom.: 12821

Bravo AF: 0.165

Asia WGS AF: 0.161 AC: 558 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	12
DANN	Benign	0.87
PhyloP100		0.38
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: rs2270570; hg19: chr9-78796522; COSMIC: COSV65089261;