NM_002594.5:c.283-18915T>C

Variant names:

• chr20-17339412-T-C
• rs6075193
• NM_002594.5:c.283-18915T>C

Variant summary

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

The NM_002594.5(PCSK2):​c.283-18915T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 151,998 control chromosomes in the GnomAD database, including 12,836 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 0.39 (12836 hom., cov: 32)
• Consequence: PCSK2 NM_002594.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.458
• 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK2	NM_002594.5	MANE Select	c.283-18915T>C		intron	N/A	NP_002585.2
	PCSK2	NM_001201528.2		c.226-18915T>C		intron	N/A	NP_001188457.1	P16519-3
	PCSK2	NM_001201529.3		c.178-18915T>C		intron	N/A	NP_001188458.1	P16519-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK2	ENST00000262545.7	TSL:1 MANE Select	c.283-18915T>C		intron	N/A	ENSP00000262545.2	P16519-1
	PCSK2	ENST00000377899.5	TSL:1	c.226-18915T>C		intron	N/A	ENSP00000367131.1	P16519-3
	PCSK2	ENST00000947703.1		c.283-18915T>C		intron	N/A	ENSP00000617762.1

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59501 AN: 151880 Hom.: 12816 Cov.: 32

Gnomad AFR AF: 0.564

Gnomad AMI AF: 0.554

Gnomad AMR AF: 0.288

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.0303

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.376

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

GnomAD4 genome AF: 0.392 AC: 59559 AN: 151998 Hom.: 12836 Cov.: 32 AF XY: 0.385 AC XY: 28628 AN XY: 74310

African (AFR) AF: 0.564 AC: 23330 AN: 41392

American (AMR) AF: 0.287 AC: 4398 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 1059 AN: 3466

East Asian (EAS) AF: 0.0299 AC: 155 AN: 5176

South Asian (SAS) AF: 0.280 AC: 1346 AN: 4814

European-Finnish (FIN) AF: 0.331 AC: 3492 AN: 10562

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.359 AC: 24371 AN: 67976

Other (OTH) AF: 0.374 AC: 789 AN: 2112

Alfa AF: 0.363 Hom.: 5415

Bravo AF: 0.395

Asia WGS AF: 0.208 AC: 725 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.1
DANN	Benign	0.30
PhyloP100		-0.46
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: rs6075193; hg19: chr20-17320057;