Genetic Variant PCSK5:c.-209G>T (chr9-75890973-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001372043.1(PCSK5):c.-209G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0945 in 410,616 control chromosomes in the GnomAD database, including 3,766 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 0.14 ( 2741 hom., cov: 33)

Exomes 𝑓: 0.068 ( 1025 hom. )

Consequence

PCSK5
NM_001372043.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.43

Publications

4 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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK5	NM_001372043.1 link	c.-209G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 38	ENST00000674117.1	NP_001358972.1
PCSK5	NM_001372043.1 link	c.-209G>T		5_prime_UTR_variant	Exon 1 of 38	ENST00000674117.1	NP_001358972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK5	ENST00000674117.1 link	c.-209G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 38		NM_001372043.1	ENSP00000500971.1		A0A669KA35
PCSK5	ENST00000674117.1 link	c.-209G>T		5_prime_UTR_variant	Exon 1 of 38		NM_001372043.1	ENSP00000500971.1		A0A669KA35

Frequencies

GnomAD3 genomes

AF:

0.139

AC:

21177

AN:

152002

Hom.:

2737

Cov.:

show subpopulations

Gnomad AFR

AF:

0.339

Gnomad AMI

AF:

0.0548

Gnomad AMR

AF:

0.0736

Gnomad ASJ

AF:

0.0499

Gnomad EAS

AF:

0.000775

Gnomad SAS

AF:

0.0219

Gnomad FIN

AF:

0.0906

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.0652

Gnomad OTH

AF:

0.119

GnomAD4 exome

AF:

0.0681

AC:

17607

AN:

258500

Hom.:

1025

Cov.:

AF XY:

0.0656

AC XY:

8657

AN XY:

132010

show subpopulations

African (AFR)

AF:

0.338

AC:

2366

AN:

7004

American (AMR)

AF:

0.0664

AC:

469

AN:

7060

Ashkenazi Jewish (ASJ)

AF:

0.0527

AC:

478

AN:

9066

East Asian (EAS)

AF:

0.00

AC:

AN:

22264

South Asian (SAS)

AF:

0.0267

AC:

162

AN:

6076

European-Finnish (FIN)

AF:

0.0856

AC:

1836

AN:

21452

Middle Eastern (MID)

AF:

0.0862

AC:

115

AN:

1334

European-Non Finnish (NFE)

AF:

0.0640

AC:

10725

AN:

167518

Other (OTH)

AF:

0.0871

AC:

1456

AN:

16726

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

719

1438

2156

2875

3594

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.139

AC:

21194

AN:

152116

Hom.:

2741

Cov.:

AF XY:

0.137

AC XY:

10208

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.339

AC:

14050

AN:

41492

American (AMR)

AF:

0.0734

AC:

1123

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0499

AC:

173

AN:

3470

East Asian (EAS)

AF:

0.000972

AC:

AN:

5146

South Asian (SAS)

AF:

0.0217

AC:

105

AN:

4828

European-Finnish (FIN)

AF:

0.0906

AC:

960

AN:

10592

Middle Eastern (MID)

AF:

0.156

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0652

AC:

4433

AN:

67982

Other (OTH)

AF:

0.118

AC:

249

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

817

1634

2451

3268

4085

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

208

416

624

832

1040

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0484

Hom.:

Bravo

AF:

0.148

Asia WGS

AF:

0.0290

AC:

100

AN:

3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

5.7

(source)

DANN

Benign

0.84

PhyloP100

-1.4

PromoterAI

-0.066

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over