5-96429259-C-T

Position:

chr5-96429259-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000439.5(PCSK1):c.239G>A(p.Arg80Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00064 in 1,604,620 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0011 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 6 hom. )

Consequence

PCSK1
NM_000439.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.09

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006049186).

BP6

Variant 5-96429259-C-T is Benign according to our data. Variant chr5-96429259-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1336021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00106 (161/152198) while in subpopulation EAS AF= 0.0297 (154/5180). AF 95% confidence interval is 0.0259. There are 2 homozygotes in gnomad4. There are 89 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 161 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK1	NM_000439.5 linkuse as main transcript	c.239G>A	p.Arg80Gln	missense_variant	2/14	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.239G>A	p.Arg80Gln	missense_variant	2/14	1	NM_000439.5	ENSP00000308024.2	P29120-1
PCSK1	ENST00000508626.5 linkuse as main transcript	c.98G>A	p.Arg33Gln	missense_variant	2/14	2		ENSP00000421600.1	P29120-2
PCSK1	ENST00000509190.1 linkuse as main transcript	c.239G>A	p.Arg80Gln	missense_variant	3/5	4		ENSP00000427294.1	D6RJA3
ENSG00000251314	ENST00000502645.2 linkuse as main transcript	n.354+49607C>T		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00107

AC:

163

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0300

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.00209

AC:

526

AN:

251106

Hom.:

AF XY:

0.00190

AC XY:

258

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0273

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000596

AC:

866

AN:

1452422

Hom.:

Cov.:

AF XY:

0.000589

AC XY:

426

AN XY:

723328

show subpopulations

Gnomad4 AFR exome

AF:

0.0000901

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0188

Gnomad4 SAS exome

AF:

0.000500

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000154

Gnomad4 OTH exome

AF:

0.000982

GnomAD4 genome

AF:

0.00106

AC:

161

AN:

152198

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0297

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.000741

Hom.:

Bravo

AF:

0.00112

ExAC

AF:

0.00202

AC:

245

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 20, 2017

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

T;.;T

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.93

D;D;D

MetaRNN

Benign

0.0060

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Pathogenic

3.0

M;.;.

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.8

N;N;N

REVEL

Benign

0.21

Sift

Benign

0.24

T;T;D

Sift4G

Benign

0.28

T;T;.

Polyphen

0.99

D;.;.

Vest4

0.35

MVP

0.76

MPC

0.72

ClinPred

0.15

GERP RS

5.8

Varity_R

0.48

gMVP

0.37

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

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