chr20-17360532-A-T

Position:

chr20-17360532-A-T

Variant summary

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

The NM_002594.5(PCSK2):c.397A>T(p.Ile133Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000125 in 1,598,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PCSK2
NM_002594.5 missense, splice_region

Scores

Splicing: ADA: 0.002211

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.21

Variant links:

Genes affected

PCSK2 (HGNC:8744): (proprotein convertase subtilisin/kexin type 2) 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 protein undergoes an initial autocatalytic processing event and interacts with a neuroendocrine secretory protein in the ER, exits the ER and sorts to secretory granules, where it is cleaved and catalytically activated during intracellular transport. The encoded 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. Single nucleotide polymorphisms in this gene may increase susceptibility to myocardial infarction and type 2 diabetes. This gene may also play a role in tumor development and progression. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2014]

PCSK2 links:

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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=0.14596301).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PCSK2	NM_002594.5 linkuse as main transcript	c.397A>T	p.Ile133Phe	missense_variant, splice_region_variant	4/12	ENST00000262545.7	NP_002585.2
PCSK2	NM_001201528.2 linkuse as main transcript	c.340A>T	p.Ile114Phe	missense_variant, splice_region_variant	5/13		NP_001188457.1
PCSK2	NM_001201529.3 linkuse as main transcript	c.292A>T	p.Ile98Phe	missense_variant, splice_region_variant	3/11		NP_001188458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK2	ENST00000262545.7 linkuse as main transcript	c.397A>T	p.Ile133Phe	missense_variant, splice_region_variant	4/12	1	NM_002594.5	ENSP00000262545	P1	P16519-1
PCSK2	ENST00000377899.5 linkuse as main transcript	c.340A>T	p.Ile114Phe	missense_variant, splice_region_variant	5/13	1		ENSP00000367131		P16519-3
PCSK2	ENST00000536609.1 linkuse as main transcript	c.292A>T	p.Ile98Phe	missense_variant, splice_region_variant	3/11	2		ENSP00000437458		P16519-2
PCSK2	ENST00000470007.1 linkuse as main transcript	n.392A>T		splice_region_variant, non_coding_transcript_exon_variant	4/6	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000407

AC:

AN:

245700

Hom.:

AF XY:

0.00000754

AC XY:

AN XY:

132610

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000553

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:

6.92e-7

AC:

AN:

1446108

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719856

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

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:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2023

The c.397A>T (p.I133F) alteration is located in exon 4 (coding exon 4) of the PCSK2 gene. This alteration results from a A to T substitution at nucleotide position 397, causing the isoleucine (I) at amino acid position 133 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.61

DEOGEN2

Benign

0.066

.;T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

0.054

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.83

T;T;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.92

.;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

0.050

N;N;N

REVEL

Benign

0.057

Sift

Benign

0.70

T;T;T

Sift4G

Benign

0.69

T;T;T

Polyphen

0.0

.;B;.

Vest4

0.31

MutPred

0.39

.;Gain of catalytic residue at I133 (P = 0.0306);.;

MVP

0.043

MPC

1.5

ClinPred

0.10

GERP RS

4.8

Varity_R

0.11

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0022

dbscSNV1_RF

Benign

0.16

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