Genetic Variant NM_002594.5:c.10G>T (chr20-17227315-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002594.5(PCSK2):c.10G>T(p.Gly4Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. G4S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

PCSK2
NM_002594.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.05

Publications

0 publications found

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:

ENSG00000287241 (HGNC:):

ENSG00000287241 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002594.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCSK2	NM_002594.5	MANE Select	c.10G>T	p.Gly4Cys	missense	Exon 1 of 12	NP_002585.2
PCSK2	NM_001201529.3		c.10G>T	p.Gly4Cys	missense	Exon 1 of 11	NP_001188458.1	P16519-2
PCSK2	NM_001201528.2		c.-33-15G>T		intron	N/A	NP_001188457.1	P16519-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCSK2	ENST00000262545.7	TSL:1 MANE Select	c.10G>T	p.Gly4Cys	missense	Exon 1 of 12	ENSP00000262545.2	P16519-1
PCSK2	ENST00000377899.5	TSL:1	c.-33-15G>T		intron	N/A	ENSP00000367131.1	P16519-3
PCSK2	ENST00000947703.1		c.10G>T	p.Gly4Cys	missense	Exon 1 of 12	ENSP00000617762.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.069

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.76

M_CAP

Benign

0.072

MetaRNN

Uncertain

0.59

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.90

PhyloP100

6.1

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.37

REVEL

Uncertain

0.33

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.030

Polyphen

1.0

Vest4

0.59

MutPred

0.42

Loss of disorder (P = 0.0043)

MVP

0.76

MPC

0.27

ClinPred

0.82

GERP RS

5.4

PromoterAI

0.051

Neutral

(source)

Varity_R

0.22

gMVP

0.82

Mutation Taster

=85/15

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over