chr9-75891248-G-C

Variant names:

• chr9-75891248-G-C
• rs1000064216
• NM_001372043.1:c.67G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001372043.1(PCSK5):​c.67G>C​(p.Gly23Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PCSK5 NM_001372043.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1682989).

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.67G>C	p.Gly23Arg	missense	Exon 1 of 38	NP_001358972.1	A0A669KA35
	PCSK5	NM_001190482.2		c.67G>C	p.Gly23Arg	missense	Exon 1 of 37	NP_001177411.1	Q92824-1
	PCSK5	NM_006200.6		c.67G>C	p.Gly23Arg	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.67G>C	p.Gly23Arg	missense	Exon 1 of 38	ENSP00000500971.1	A0A669KA35
	PCSK5	ENST00000376752.9	TSL:1	c.67G>C	p.Gly23Arg	missense	Exon 1 of 21	ENSP00000365943.4	Q92824-2
	PCSK5	ENST00000854198.1		c.67G>C	p.Gly23Arg	missense	Exon 1 of 38	ENSP00000524257.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.11
Sift	Benign	0.35	T
Sift4G	Benign	0.36	T
Polyphen		0.026	B
Vest4		0.22
MutPred		0.63		Gain of methylation at G23 (P = 0.0175)
MVP		0.56
MPC		1.5
ClinPred		0.33	T
GERP RS		1.9
Varity_R		0.099
gMVP		0.57
Mutation Taster		=87/13	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: rs1000064216; hg19: chr9-78506164;