rs6232

Positions:

chr5-96416081-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000439.5(PCSK1):c.661A>G(p.Asn221Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0451 in 1,612,350 control chromosomes in the GnomAD database, including 1,870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 103 hom., cov: 33)

Exomes 𝑓: 0.046 ( 1767 hom. )

Consequence

PCSK1
NM_000439.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 5.67

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 links:

ENSG00000251314 (HGNC:):

ENSG00000251314 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012222022).

BP6

Variant 5-96416081-T-C is Benign according to our data. Variant chr5-96416081-T-C is described in ClinVar as [Benign]. Clinvar id is 14040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-96416081-T-C is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK1	NM_000439.5 linkuse as main transcript	c.661A>G	p.Asn221Asp	missense_variant	6/14	ENST00000311106.8	NP_000430.3	P29120-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PCSK1	ENST00000311106.8 linkuse as main transcript	c.661A>G	p.Asn221Asp	missense_variant	6/14	1	NM_000439.5	ENSP00000308024.2	P29120-1
PCSK1	ENST00000508626.5 linkuse as main transcript	c.520A>G	p.Asn174Asp	missense_variant	6/14	2		ENSP00000421600.1	P29120-2
ENSG00000251314	ENST00000502645.2 linkuse as main transcript	n.354+36429T>C		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0322

AC:

4909

AN:

152228

Hom.:

105

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00924

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.0274

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.0522

Gnomad FIN

AF:

0.0247

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0499

Gnomad OTH

AF:

0.0296

GnomAD3 exomes

AF:

0.0386

AC:

9706

AN:

251438

Hom.:

252

AF XY:

0.0420

AC XY:

5702

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00818

Gnomad AMR exome

AF:

0.0147

Gnomad ASJ exome

AF:

0.0173

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.0661

Gnomad FIN exome

AF:

0.0309

Gnomad NFE exome

AF:

0.0525

Gnomad OTH exome

AF:

0.0370

GnomAD4 exome

AF:

0.0465

AC:

67823

AN:

1460004

Hom.:

1767

Cov.:

AF XY:

0.0472

AC XY:

34289

AN XY:

726458

show subpopulations

Gnomad4 AFR exome

AF:

0.00792

Gnomad4 AMR exome

AF:

0.0164

Gnomad4 ASJ exome

AF:

0.0169

Gnomad4 EAS exome

AF:

0.000479

Gnomad4 SAS exome

AF:

0.0663

Gnomad4 FIN exome

AF:

0.0336

Gnomad4 NFE exome

AF:

0.0506

Gnomad4 OTH exome

AF:

0.0389

GnomAD4 genome

AF:

0.0322

AC:

4903

AN:

152346

Hom.:

103

Cov.:

AF XY:

0.0313

AC XY:

2331

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00921

Gnomad4 AMR

AF:

0.0274

Gnomad4 ASJ

AF:

0.0164

Gnomad4 EAS

AF:

0.00173

Gnomad4 SAS

AF:

0.0514

Gnomad4 FIN

AF:

0.0247

Gnomad4 NFE

AF:

0.0499

Gnomad4 OTH

AF:

0.0298

Alfa

AF:

0.0469

Hom.:

506

Bravo

AF:

0.0316

TwinsUK

AF:

0.0496

AC:

184

ALSPAC

AF:

0.0589

AC:

227

ESP6500AA

AF:

0.00999

AC:

ESP6500EA

AF:

0.0501

AC:

431

ExAC

AF:

0.0399

AC:

4842

Asia WGS

AF:

0.0210

AC:

AN:

3478

EpiCase

AF:

0.0505

EpiControl

AF:

0.0507

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 18, 2018	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2021	This variant is associated with the following publications: (PMID: 31504391, 28271036, 18604207, 23383060, 22000902, 25784503, 19528091) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Body mass index quantitative trait locus 12

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Aug 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;.

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.91

D;D

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

1.3

L;.

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-4.0

D;D

REVEL

Uncertain

0.45

Sift

Benign

0.12

T;T

Sift4G

Benign

0.19

T;T

Polyphen

0.036

B;.

Vest4

0.080

MPC

0.30

ClinPred

0.031

GERP RS

6.1

Varity_R

0.61

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over