20-17465549-C-T

Position:

• chr20-17465549-C-T

Variant summary

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

The NM_002594.5(PCSK2):​c.1426C>T​(p.Pro476Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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)
• Consequence: PCSK2 NM_002594.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94

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=0.11972365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK2	NM_002594.5	c.1426C>T	p.Pro476Ser	missense_variant	11/12	ENST00000262545.7	NP_002585.2
PCSK2	NM_001201528.2	c.1369C>T	p.Pro457Ser	missense_variant	12/13		NP_001188457.1
PCSK2	NM_001201529.3	c.1321C>T	p.Pro441Ser	missense_variant	10/11		NP_001188458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK2	ENST00000262545.7	c.1426C>T	p.Pro476Ser	missense_variant	11/12	1	NM_002594.5	ENSP00000262545	P1
PCSK2	ENST00000377899.5	c.1369C>T	p.Pro457Ser	missense_variant	12/13	1		ENSP00000367131
PCSK2	ENST00000536609.1	c.1321C>T	p.Pro441Ser	missense_variant	10/11	2		ENSP00000437458
PCSK2	ENST00000459871.1	n.2117C>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000444 AC: 1 AN: 225360 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 120486

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

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 Cov.: 28

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2023

The c.1426C>T (p.P476S) alteration is located in exon 11 (coding exon 11) of the PCSK2 gene. This alteration results from a C to T substitution at nucleotide position 1426, causing the proline (P) at amino acid position 476 to be replaced by a serine (S). 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	0.069
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	.;T;.
Eigen	Benign	0.0018
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.6	.;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.18
MutPred		0.28		.;Loss of methylation at K478 (P = 0.0782);.;
MVP		0.40
MPC		1.0
ClinPred		0.67	D
GERP RS		5.7
Varity_R		0.11
gMVP		0.57

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

LitVar

Other links and lift over

dbSNP: rs749157367; hg19: chr20-17446194; COSMIC: COSV52728531;