rs1799904

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000439.5(PCSK1):​c.239G>T​(p.Arg80Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000249 in 1,604,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R80Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PCSK1
NM_000439.5 missense

Scores

7
12

Clinical Significance

Not reported in ClinVar

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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2337).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PCSK1NM_000439.5 linkuse as main transcriptc.239G>T p.Arg80Leu missense_variant 2/14 ENST00000311106.8 NP_000430.3 P29120-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PCSK1ENST00000311106.8 linkuse as main transcriptc.239G>T p.Arg80Leu missense_variant 2/141 NM_000439.5 ENSP00000308024.2 P29120-1
PCSK1ENST00000508626.5 linkuse as main transcriptc.98G>T p.Arg33Leu missense_variant 2/142 ENSP00000421600.1 P29120-2
PCSK1ENST00000509190.1 linkuse as main transcriptc.239G>T p.Arg80Leu missense_variant 3/54 ENSP00000427294.1 D6RJA3
ENSG00000251314ENST00000502645.2 linkuse as main transcriptn.354+49607C>A intron_variant 5

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152080
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251106
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135700
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.89e-7
AC:
1
AN:
1452426
Hom.:
0
Cov.:
26
AF XY:
0.00000138
AC XY:
1
AN XY:
723328
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152080
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74278
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000479
Alfa
AF:
0.00000463
Hom.:
2
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.43
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.39
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.21
T;.;T
Eigen
Benign
0.13
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.95
D;D;D
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.23
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.0
L;.;.
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-2.4
N;D;D
REVEL
Benign
0.075
Sift
Benign
0.61
T;T;D
Sift4G
Benign
0.29
T;T;.
Polyphen
0.47
P;.;.
Vest4
0.52
MVP
0.60
MPC
0.87
ClinPred
0.46
T
GERP RS
5.8
Varity_R
0.32
gMVP
0.53

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs1799904; hg19: chr5-95764963; API