chr20-17260314-C-A

Position:

• chr20-17260314-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.354

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]

LOC105372546 (HGNC:):

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=0.08969119).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK2	NM_002594.5	c.252C>A	p.His84Gln	missense_variant	2/12	ENST00000262545.7	NP_002585.2
LOC105372546	XR_007067540.1	n.253+3750G>T		intron_variant, non_coding_transcript_variant
PCSK2	NM_001201528.2	c.195C>A	p.His65Gln	missense_variant	3/13		NP_001188457.1
PCSK2	NM_001201529.3	c.177+32832C>A		intron_variant			NP_001188458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK2	ENST00000262545.7	c.252C>A	p.His84Gln	missense_variant	2/12	1	NM_002594.5	ENSP00000262545	P1
PCSK2	ENST00000377899.5	c.195C>A	p.His65Gln	missense_variant	3/13	1		ENSP00000367131
PCSK2	ENST00000536609.1	c.177+32832C>A		intron_variant		2		ENSP00000437458
PCSK2	ENST00000470007.1	n.247C>A		non_coding_transcript_exon_variant	2/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461118 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726926

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.: 32

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

Mar 29, 2022

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	T
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	N
LIST_S2	Benign	0.34	T;T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.090	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	.;N
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.37	T
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	T
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.

Other links and lift over

hg19: chr20-17240959;