9-76189788-G-A

Variant names:

• chr9-76189788-G-A
• rs10869726
• NM_001372043.1:c.2626+42G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001372043.1(PCSK5):​c.2626+42G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,011,794 control chromosomes in the GnomAD database, including 8,646 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 0.15 (1970 hom., cov: 32)
  • Exomes 𝑓: 0.12 (6676 hom.)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.399
• Publications: 4 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=-0.77).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 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.2626+42G>A		intron	N/A	NP_001358972.1	A0A669KA35
	PCSK5	NM_001190482.2		c.2626+42G>A		intron	N/A	NP_001177411.1	Q92824-1
	PCSK5	NM_006200.6		c.2626+42G>A		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.2626+42G>A		intron	N/A	ENSP00000500971.1	A0A669KA35
	PCSK5	ENST00000376752.9	TSL:1	c.2626+42G>A		intron	N/A	ENSP00000365943.4	Q92824-2
	PCSK5	ENST00000854198.1		c.2626+42G>A		intron	N/A	ENSP00000524257.1

Frequencies

GnomAD3 genomes AF: 0.153 AC: 22645 AN: 147924 Hom.: 1967 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.0949

Gnomad AMR AF: 0.0957

Gnomad ASJ AF: 0.0899

Gnomad EAS AF: 0.0825

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.145

GnomAD2 exomes AF: 0.127 AC: 26136 AN: 205320 AF XY: 0.127

Gnomad AFR exome AF: 0.251

Gnomad AMR exome AF: 0.0731

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.0854

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.120 AC: 103249 AN: 863752 Hom.: 6676 Cov.: 12 AF XY: 0.120 AC XY: 54036 AN XY: 451588

African (AFR) AF: 0.252 AC: 5483 AN: 21750

American (AMR) AF: 0.0722 AC: 2813 AN: 38950

Ashkenazi Jewish (ASJ) AF: 0.0884 AC: 1874 AN: 21206

East Asian (EAS) AF: 0.0953 AC: 3507 AN: 36786

South Asian (SAS) AF: 0.0962 AC: 6726 AN: 69916

European-Finnish (FIN) AF: 0.117 AC: 6052 AN: 51850

Middle Eastern (MID) AF: 0.187 AC: 855 AN: 4584

European-Non Finnish (NFE) AF: 0.123 AC: 70954 AN: 578192

Other (OTH) AF: 0.123 AC: 4985 AN: 40518

GnomAD4 genome AF: 0.153 AC: 22674 AN: 148042 Hom.: 1970 Cov.: 32 AF XY: 0.151 AC XY: 10945 AN XY: 72364

African (AFR) AF: 0.246 AC: 10103 AN: 41078

American (AMR) AF: 0.0956 AC: 1414 AN: 14798

Ashkenazi Jewish (ASJ) AF: 0.0899 AC: 302 AN: 3360

East Asian (EAS) AF: 0.0827 AC: 427 AN: 5162

South Asian (SAS) AF: 0.107 AC: 504 AN: 4722

European-Finnish (FIN) AF: 0.109 AC: 1102 AN: 10142

Middle Eastern (MID) AF: 0.262 AC: 75 AN: 286

European-Non Finnish (NFE) AF: 0.127 AC: 8357 AN: 65548

Other (OTH) AF: 0.149 AC: 304 AN: 2040

Alfa AF: 0.128 Hom.: 3886

Bravo AF: 0.153

Asia WGS AF: 0.111 AC: 384 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.4
DANN	Benign	0.80
PhyloP100		-0.40
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: rs10869726; hg19: chr9-78804704; COSMIC: COSV65085552;