chr9-75891229-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_001372043.1(PCSK5):​c.48G>A​(p.Leu16=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0748 in 1,518,016 control chromosomes in the GnomAD database, including 6,709 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 0.13 ( 2348 hom., cov: 33)
Exomes 𝑓: 0.069 ( 4361 hom. )

Consequence

PCSK5
NM_001372043.1 synonymous

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.855
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP7
Synonymous conserved (PhyloP=0.855 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PCSK5NM_001372043.1 linkuse as main transcriptc.48G>A p.Leu16= synonymous_variant 1/38 ENST00000674117.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PCSK5ENST00000674117.1 linkuse as main transcriptc.48G>A p.Leu16= synonymous_variant 1/38 NM_001372043.1 A2
PCSK5ENST00000376752.9 linkuse as main transcriptc.48G>A p.Leu16= synonymous_variant 1/211 Q92824-2
PCSK5ENST00000545128.5 linkuse as main transcriptc.48G>A p.Leu16= synonymous_variant 1/375 P4Q92824-1
PCSK5ENST00000376767.7 linkuse as main transcriptn.560G>A non_coding_transcript_exon_variant 1/142

Frequencies

GnomAD3 genomes
AF:
0.131
AC:
19875
AN:
152072
Hom.:
2345
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.309
Gnomad AMI
AF:
0.0548
Gnomad AMR
AF:
0.0703
Gnomad ASJ
AF:
0.0470
Gnomad EAS
AF:
0.000776
Gnomad SAS
AF:
0.0219
Gnomad FIN
AF:
0.0908
Gnomad MID
AF:
0.143
Gnomad NFE
AF:
0.0651
Gnomad OTH
AF:
0.114
GnomAD3 exomes
AF:
0.0713
AC:
11845
AN:
166054
Hom.:
809
AF XY:
0.0658
AC XY:
6101
AN XY:
92710
show subpopulations
Gnomad AFR exome
AF:
0.307
Gnomad AMR exome
AF:
0.0358
Gnomad ASJ exome
AF:
0.0525
Gnomad EAS exome
AF:
0.000113
Gnomad SAS exome
AF:
0.0220
Gnomad FIN exome
AF:
0.0882
Gnomad NFE exome
AF:
0.0652
Gnomad OTH exome
AF:
0.0726
GnomAD4 exome
AF:
0.0686
AC:
93668
AN:
1365826
Hom.:
4361
Cov.:
31
AF XY:
0.0668
AC XY:
45174
AN XY:
676764
show subpopulations
Gnomad4 AFR exome
AF:
0.320
Gnomad4 AMR exome
AF:
0.0451
Gnomad4 ASJ exome
AF:
0.0512
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0239
Gnomad4 FIN exome
AF:
0.0849
Gnomad4 NFE exome
AF:
0.0670
Gnomad4 OTH exome
AF:
0.0734
GnomAD4 genome
AF:
0.131
AC:
19886
AN:
152190
Hom.:
2348
Cov.:
33
AF XY:
0.129
AC XY:
9584
AN XY:
74410
show subpopulations
Gnomad4 AFR
AF:
0.309
Gnomad4 AMR
AF:
0.0702
Gnomad4 ASJ
AF:
0.0470
Gnomad4 EAS
AF:
0.000973
Gnomad4 SAS
AF:
0.0217
Gnomad4 FIN
AF:
0.0908
Gnomad4 NFE
AF:
0.0651
Gnomad4 OTH
AF:
0.113
Alfa
AF:
0.0888
Hom.:
404
Bravo
AF:
0.138
Asia WGS
AF:
0.0270
AC:
95
AN:
3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.52
CADD
Benign
12
DANN
Benign
0.97

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs7020560; hg19: chr9-78506145; COSMIC: COSV65097645; API