NM_000439.5:c.1993C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000439.5(PCSK1):c.1993C>G(p.Gln665Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 1,613,634 control chromosomes in the GnomAD database, including 57,709 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 4653 hom., cov: 32)

Exomes 𝑓: 0.27 ( 53056 hom. )

Consequence

PCSK1
NM_000439.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.110

Publications

85 publications found

Variant links:

Genes affected

PCSK1 (HGNC:8743): (proprotein convertase subtilisin/kexin type 1) 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 and sorts to subcellular compartments where a second autocatalytic even takes place and the catalytic activity is acquired. The protease is packaged into and activated in dense core secretory granules and expressed in the neuroendocrine system and brain. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. It functions in the proteolytic activation of polypeptide hormones and neuropeptides precursors. Mutations in this gene have been associated with susceptibility to obesity and proprotein convertase 1/3 deficiency. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene [provided by RefSeq, Jan 2014]

PCSK1 links:

CAST (HGNC:1515): (calpastatin) The protein encoded by this gene is an endogenous calpain (calcium-dependent cysteine protease) inhibitor. It consists of an N-terminal domain L and four repetitive calpain-inhibition domains (domains 1-4), and it is involved in the proteolysis of amyloid precursor protein. The calpain/calpastatin system is involved in numerous membrane fusion events, such as neural vesicle exocytosis and platelet and red-cell aggregation. The encoded protein is also thought to affect the expression levels of genes encoding structural or regulatory proteins. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2010]

CAST Gene-Disease associations (from GenCC):

peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp

CAST links:

CAST (HGNC:):

CAST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003394097).

BP6

Variant 5-96393270-G-C is Benign according to our data. Variant chr5-96393270-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 354640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK1	NM_000439.5 link	c.1993C>G	p.Gln665Glu	missense_variant	Exon 14 of 14	ENST00000311106.8	NP_000430.3	P29120-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK1	ENST00000311106.8 link	c.1993C>G	p.Gln665Glu	missense_variant	Exon 14 of 14	1	NM_000439.5	ENSP00000308024.2		P29120-1

Frequencies

GnomAD3 genomes

AF:

0.243

AC:

36901

AN:

151924

Hom.:

4658

Cov.:

show subpopulations

Gnomad AFR

AF:

0.191

Gnomad AMI

AF:

0.155

Gnomad AMR

AF:

0.205

Gnomad ASJ

AF:

0.279

Gnomad EAS

AF:

0.308

Gnomad SAS

AF:

0.310

Gnomad FIN

AF:

0.278

Gnomad MID

AF:

0.247

Gnomad NFE

AF:

0.267

Gnomad OTH

AF:

0.251

GnomAD2 exomes

AF:

0.266

AC:

66704

AN:

251072

AF XY:

0.271

show subpopulations

Gnomad AFR exome

AF:

0.188

Gnomad AMR exome

AF:

0.200

Gnomad ASJ exome

AF:

0.287

Gnomad EAS exome

AF:

0.308

Gnomad FIN exome

AF:

0.285

Gnomad NFE exome

AF:

0.274

Gnomad OTH exome

AF:

0.258

GnomAD4 exome

AF:

0.268

AC:

391365

AN:

1461592

Hom.:

53056

Cov.:

AF XY:

0.269

AC XY:

195692

AN XY:

727100

show subpopulations

African (AFR)

AF:

0.183

AC:

6126

AN:

33452

American (AMR)

AF:

0.199

AC:

8876

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.292

AC:

7640

AN:

26120

East Asian (EAS)

AF:

0.263

AC:

10449

AN:

39698

South Asian (SAS)

AF:

0.305

AC:

26330

AN:

86248

European-Finnish (FIN)

AF:

0.285

AC:

15204

AN:

53416

Middle Eastern (MID)

AF:

0.236

AC:

1361

AN:

5768

European-Non Finnish (NFE)

AF:

0.269

AC:

299352

AN:

1111820

Other (OTH)

AF:

0.265

AC:

16027

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

16486

32971

49457

65942

82428

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10052

20104

30156

40208

50260

<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:

0.243

AC:

36892

AN:

152042

Hom.:

4653

Cov.:

AF XY:

0.242

AC XY:

17999

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.191

AC:

7905

AN:

41468

American (AMR)

AF:

0.205

AC:

3134

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.279

AC:

968

AN:

3468

East Asian (EAS)

AF:

0.307

AC:

1584

AN:

5158

South Asian (SAS)

AF:

0.310

AC:

1490

AN:

4806

European-Finnish (FIN)

AF:

0.278

AC:

2932

AN:

10564

Middle Eastern (MID)

AF:

0.241

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.267

AC:

18140

AN:

67980

Other (OTH)

AF:

0.250

AC:

527

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1409

2818

4226

5635

7044

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

388

776

1164

1552

1940

<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:

0.265

Hom.:

4212

Bravo

AF:

0.238

TwinsUK

AF:

0.272

AC:

1009

ALSPAC

AF:

0.288

AC:

1109

ESP6500AA

AF:

0.193

AC:

849

ESP6500EA

AF:

0.279

AC:

2397

ExAC

AF:

0.269

AC:

32618

Asia WGS

AF:

0.280

AC:

973

AN:

3478

EpiCase

AF:

0.269

EpiControl

AF:

0.276

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Dec 19, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

May 26, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28271036, 23383060, 25625282, 24932808) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Monogenic Non-Syndromic Obesity

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Obesity due to prohormone convertase I deficiency

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.062

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.016

T;T

MetaRNN

Benign

0.0034

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.69

N;.

PhyloP100

0.11

PrimateAI

Benign

0.30

PROVEAN

Benign

0.13

N;N

REVEL

Benign

0.081

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.011

MPC

0.28

ClinPred

0.0016

GERP RS

-0.27

Varity_R

0.031

gMVP

0.11

Mutation Taster

=100/0

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over