9-75891273-G-C

Variant names:

• chr9-75891273-G-C
• rs147273947
• NM_001372043.1:c.92G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001372043.1(PCSK5):​c.92G>C​(p.Arg31Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000726 in 1,377,826 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R31L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: PCSK5 NM_001372043.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.22
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.92G>C	p.Arg31Pro	missense	Exon 1 of 38	NP_001358972.1	A0A669KA35
	PCSK5	NM_001190482.2		c.92G>C	p.Arg31Pro	missense	Exon 1 of 37	NP_001177411.1	Q92824-1
	PCSK5	NM_006200.6		c.92G>C	p.Arg31Pro	missense	Exon 1 of 21	NP_006191.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK5	ENST00000674117.1	MANE Select	c.92G>C	p.Arg31Pro	missense	Exon 1 of 38	ENSP00000500971.1	A0A669KA35
	PCSK5	ENST00000376752.9	TSL:1	c.92G>C	p.Arg31Pro	missense	Exon 1 of 21	ENSP00000365943.4	Q92824-2
	PCSK5	ENST00000854198.1		c.92G>C	p.Arg31Pro	missense	Exon 1 of 38	ENSP00000524257.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.26e-7 AC: 1 AN: 1377826 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 683952

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27290

American (AMR) AF: 0.00 AC: 0 AN: 25738

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23302

East Asian (EAS) AF: 0.00 AC: 0 AN: 32702

South Asian (SAS) AF: 0.00 AC: 0 AN: 73454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52224

Middle Eastern (MID) AF: 0.000181 AC: 1 AN: 5528

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080732

Other (OTH) AF: 0.00 AC: 0 AN: 56856

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.2	L
PhyloP100		5.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.19
Sift	Benign	0.034	D
Sift4G	Uncertain	0.050	T
Polyphen		0.81	P
Vest4		0.53
MutPred		0.60		Loss of sheet (P = 0.0315)
MVP		0.73
MPC		2.4
ClinPred		0.92	D
GERP RS		5.0
Varity_R		0.59
gMVP		0.63
Mutation Taster		=54/46	polymorphism

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: rs147273947; hg19: chr9-78506189;