9-76023814-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001372043.1(PCSK5):c.488A>G(p.Lys163Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PCSK5 NM_001372043.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.97

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3557129).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK5	NM_001372043.1	c.488A>G	p.Lys163Arg	missense_variant	4/38	ENST00000674117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK5	ENST00000674117.1	c.488A>G	p.Lys163Arg	missense_variant	4/38		NM_001372043.1	A2
PCSK5	ENST00000376752.9	c.488A>G	p.Lys163Arg	missense_variant	4/21	1
PCSK5	ENST00000545128.5	c.488A>G	p.Lys163Arg	missense_variant	4/37	5		P4
PCSK5	ENST00000376767.7	n.1000A>G		non_coding_transcript_exon_variant	4/14	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251008 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135654

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461370 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726996

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2023

The c.488A>G (p.K163R) alteration is located in exon 4 (coding exon 4) of the PCSK5 gene. This alteration results from a A to G substitution at nucleotide position 488, causing the lysine (K) at amino acid position 163 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.7	L;.;L
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.036	D;T;T
Sift4G	Uncertain	0.039	D;T;T
Polyphen		0.011, 0.0020	.;B;B
Vest4		0.19
MutPred		0.57		Loss of ubiquitination at K163 (P = 0.0446);Loss of ubiquitination at K163 (P = 0.0446);Loss of ubiquitination at K163 (P = 0.0446);
MVP		0.74
MPC		1.0
ClinPred		0.73	D
GERP RS		4.6
Varity_R		0.16
gMVP		0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs1279448190; hg19: chr9-78638730;