Genetic Variant NM_001372043.1:c.34C>G (chr9-75891215-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001372043.1(PCSK5):c.34C>G(p.Arg12Gly) 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. 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. R12C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

PCSK5
NM_001372043.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.15

Publications

1 publications found

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]

PCSK5 Gene-Disease associations (from GenCC):

syndromic congenital heart disease
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

PCSK5 links:

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ACMG classification

Classification was made for transcript

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=0.17732501).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCSK5	NM_001372043.1	MANE Select	c.34C>G	p.Arg12Gly	missense	Exon 1 of 38	NP_001358972.1	A0A669KA35
PCSK5	NM_001190482.2		c.34C>G	p.Arg12Gly	missense	Exon 1 of 37	NP_001177411.1	Q92824-1
PCSK5	NM_006200.6		c.34C>G	p.Arg12Gly	missense	Exon 1 of 21	NP_006191.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCSK5	ENST00000674117.1	MANE Select	c.34C>G	p.Arg12Gly	missense	Exon 1 of 38	ENSP00000500971.1	A0A669KA35
PCSK5	ENST00000376752.9	TSL:1	c.34C>G	p.Arg12Gly	missense	Exon 1 of 21	ENSP00000365943.4	Q92824-2
PCSK5	ENST00000854198.1		c.34C>G	p.Arg12Gly	missense	Exon 1 of 38	ENSP00000524257.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000643

AC:

AN:

155578

AF XY:

0.0000115

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000126

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Benign

-0.12

Eigen_PC

Benign

0.062

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.71

M_CAP

Benign

0.038

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.2

PhyloP100

3.2

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.18

Sift

Benign

0.069

Sift4G

Uncertain

0.018

Polyphen

0.093

Vest4

0.15

MutPred

0.56

Loss of methylation at R12 (P = 0.0222)

MVP

0.65

MPC

1.1

ClinPred

0.91

GERP RS

5.0

Varity_R

0.27

gMVP

0.70

Mutation Taster

=83/17

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over