20-17349080-C-T

Variant names:

• chr20-17349080-C-T
• rs737141
• NM_002594.5:c.283-9247C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002594.5(PCSK2):​c.283-9247C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 152,100 control chromosomes in the GnomAD database, including 2,444 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2444 hom., cov: 32)
• Consequence: PCSK2 NM_002594.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.384
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK2	NM_002594.5	c.283-9247C>T		intron_variant	Intron 2 of 11	ENST00000262545.7	NP_002585.2
PCSK2	NM_001201528.2	c.226-9247C>T		intron_variant	Intron 3 of 12		NP_001188457.1
PCSK2	NM_001201529.3	c.178-9247C>T		intron_variant	Intron 1 of 10		NP_001188458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK2	ENST00000262545.7	c.283-9247C>T		intron_variant	Intron 2 of 11	1	NM_002594.5	ENSP00000262545.2
PCSK2	ENST00000377899.5	c.226-9247C>T		intron_variant	Intron 3 of 12	1		ENSP00000367131.1
PCSK2	ENST00000536609.1	c.178-9247C>T		intron_variant	Intron 1 of 10	2		ENSP00000437458.1
PCSK2	ENST00000470007.1	n.278-9247C>T		intron_variant	Intron 2 of 5	3

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25361 AN: 151982 Hom.: 2439 Cov.: 32

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.0928

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.172

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.167 AC: 25393 AN: 152100 Hom.: 2444 Cov.: 32 AF XY: 0.164 AC XY: 12195 AN XY: 74364

African (AFR) AF: 0.256 AC: 10611 AN: 41482

American (AMR) AF: 0.139 AC: 2122 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 473 AN: 3472

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5162

South Asian (SAS) AF: 0.0933 AC: 450 AN: 4824

European-Finnish (FIN) AF: 0.120 AC: 1270 AN: 10582

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 9982 AN: 67964

Other (OTH) AF: 0.172 AC: 363 AN: 2112

Alfa AF: 0.137 Hom.: 1011

Bravo AF: 0.172

Asia WGS AF: 0.0770 AC: 272 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.6
DANN	Benign	0.60
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs737141; hg19: chr20-17329725;