Genetic Variant NM_002594.5:c.252C>A (chr20-17260314-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_002594.5(PCSK2):c.252C>A(p.His84Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PCSK2
NM_002594.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.354

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:

LOC105372546 (HGNC:):

LOC105372546 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=0.08969119).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK2	NM_002594.5 link	c.252C>A	p.His84Gln	missense_variant	Exon 2 of 12	ENST00000262545.7	NP_002585.2	P16519-1
PCSK2	NM_001201528.2 link	c.195C>A	p.His65Gln	missense_variant	Exon 3 of 13		NP_001188457.1	P16519-3
PCSK2	NM_001201529.3 link	c.177+32832C>A		intron_variant	Intron 1 of 10		NP_001188458.1	P16519-2
LOC105372546	XR_007067540.1 link	n.253+3750G>T		intron_variant	Intron 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PCSK2	ENST00000262545.7 link	c.252C>A	p.His84Gln	missense_variant	Exon 2 of 12	1	NM_002594.5	ENSP00000262545.2	P16519-1
PCSK2	ENST00000377899.5 link	c.195C>A	p.His65Gln	missense_variant	Exon 3 of 13	1		ENSP00000367131.1	P16519-3
PCSK2	ENST00000536609.1 link	c.177+32832C>A		intron_variant	Intron 1 of 10	2		ENSP00000437458.1	P16519-2
PCSK2	ENST00000470007.1 link	n.247C>A		non_coding_transcript_exon_variant	Exon 2 of 6	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461118

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726926

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 29, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.252C>A (p.H84Q) alteration is located in exon 2 (coding exon 2) of the PCSK2 gene. This alteration results from a C to A substitution at nucleotide position 252, causing the histidine (H) at amino acid position 84 to be replaced by a glutamine (Q). 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

0.082

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

2.2

DANN

Benign

0.79

DEOGEN2

Benign

0.048

.;T

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.34

T;T

M_CAP

Benign

0.0093

MetaRNN

Benign

0.090

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.63

.;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.10

N;N

REVEL

Benign

0.066

Sift

Benign

0.51

T;T

Sift4G

Benign

0.57

T;T

Polyphen

0.0

.;B

Vest4

0.19

MutPred

0.30

.;Gain of MoRF binding (P = 0.1581);

MVP

0.16

MPC

0.15

ClinPred

0.18

GERP RS

-1.8

Varity_R

0.039

gMVP

0.34

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over