20-17481636-G-C

Variant names:

• chr20-17481636-G-C
• NM_002594.5:c.1483G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002594.5(PCSK2):​c.1483G>C​(p.Glu495Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: PCSK2 NM_002594.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.22

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]

ACMG classification

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=0.15826312).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK2	NM_002594.5	c.1483G>C	p.Glu495Gln	missense_variant	Exon 12 of 12	ENST00000262545.7	NP_002585.2
PCSK2	NM_001201528.2	c.1426G>C	p.Glu476Gln	missense_variant	Exon 13 of 13		NP_001188457.1
PCSK2	NM_001201529.3	c.1378G>C	p.Glu460Gln	missense_variant	Exon 11 of 11		NP_001188458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK2	ENST00000262545.7	c.1483G>C	p.Glu495Gln	missense_variant	Exon 12 of 12	1	NM_002594.5	ENSP00000262545.2
PCSK2	ENST00000377899.5	c.1426G>C	p.Glu476Gln	missense_variant	Exon 13 of 13	1		ENSP00000367131.1
PCSK2	ENST00000536609.1	c.1378G>C	p.Glu460Gln	missense_variant	Exon 11 of 11	2		ENSP00000437458.1
PCSK2	ENST00000459871.1	n.2174G>C		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1483G>C (p.E495Q) alteration is located in exon 12 (coding exon 12) of the PCSK2 gene. This alteration results from a G to C substitution at nucleotide position 1483, causing the glutamic acid (E) at amino acid position 495 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	0.077
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	.;T;.
Eigen	Benign	0.024
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.37	.;N;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.36	N;N;N
REVEL	Benign	0.047
Sift	Benign	0.40	T;T;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.0020	.;B;.
Vest4		0.077
MutPred		0.32		.;Loss of ubiquitination at K497 (P = 0.0589);.;
MVP		0.39
MPC		1.0
ClinPred		0.77	D
GERP RS		5.9
Varity_R		0.20
gMVP		0.54

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: chr20-17462281;