5-96412452-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000439.5(PCSK1):​c.748G>A​(p.Glu250Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E250E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

PCSK1
NM_000439.5 missense

Scores

16
2
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.57
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PCSK1NM_000439.5 linkc.748G>A p.Glu250Lys missense_variant Exon 7 of 14 ENST00000311106.8 NP_000430.3 P29120-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PCSK1ENST00000311106.8 linkc.748G>A p.Glu250Lys missense_variant Exon 7 of 14 1 NM_000439.5 ENSP00000308024.2 P29120-1
PCSK1ENST00000513085.1 linkn.104G>A non_coding_transcript_exon_variant Exon 2 of 8 1
PCSK1ENST00000508626.5 linkc.607G>A p.Glu203Lys missense_variant Exon 7 of 14 2 ENSP00000421600.1 P29120-2
ENSG00000251314ENST00000502645.2 linkn.354+32800C>T intron_variant Intron 4 of 4 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.80
D;.
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
1.0
D;D
M_CAP
Pathogenic
0.39
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Uncertain
0.76
D
MutationAssessor
Pathogenic
3.2
M;.
PrimateAI
Pathogenic
0.90
D
PROVEAN
Uncertain
-3.9
D;D
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.96
MutPred
0.86
Gain of ubiquitination at E250 (P = 0.0146);.;
MVP
0.96
MPC
0.99
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.96
gMVP
0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-95748156; API