Genetic Variant NM_001372043.1:c.135G>C (chr9-75891316-G-C) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_001372043.1(PCSK5):c.135G>C(p.Gly45Gly) variant causes a synonymous 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. Synonymous variant affecting the same amino acid position (i.e. G45G) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

PCSK5
NM_001372043.1 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.57

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: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP7

Synonymous conserved (PhyloP=1.57 with no splicing effect.

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.135G>C	p.Gly45Gly	synonymous	Exon 1 of 38	NP_001358972.1	A0A669KA35
PCSK5	NM_001190482.2		c.135G>C	p.Gly45Gly	synonymous	Exon 1 of 37	NP_001177411.1	Q92824-1
PCSK5	NM_006200.6		c.135G>C	p.Gly45Gly	synonymous	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.135G>C	p.Gly45Gly	synonymous	Exon 1 of 38	ENSP00000500971.1	A0A669KA35
PCSK5	ENST00000376752.9	TSL:1	c.135G>C	p.Gly45Gly	synonymous	Exon 1 of 21	ENSP00000365943.4	Q92824-2
PCSK5	ENST00000854198.1		c.135G>C	p.Gly45Gly	synonymous	Exon 1 of 38	ENSP00000524257.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

1.6

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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