rs6075193

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

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK2	NM_002594.5	c.283-18915T>C		intron_variant	Intron 2 of 11	ENST00000262545.7	NP_002585.2
PCSK2	NM_001201528.2	c.226-18915T>C		intron_variant	Intron 3 of 12		NP_001188457.1
PCSK2	NM_001201529.3	c.178-18915T>C		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.283-18915T>C		intron_variant	Intron 2 of 11	1	NM_002594.5	ENSP00000262545.2
PCSK2	ENST00000377899.5	c.226-18915T>C		intron_variant	Intron 3 of 12	1		ENSP00000367131.1
PCSK2	ENST00000536609.1	c.178-18915T>C		intron_variant	Intron 1 of 10	2		ENSP00000437458.1
PCSK2	ENST00000470007.1	n.278-18915T>C		intron_variant	Intron 2 of 5	3

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

Gnomad4 AFR AF: 0.564 AC: 0.563635 AN: 0.563635

Gnomad4 AMR AF: 0.287 AC: 0.287489 AN: 0.287489

Gnomad4 ASJ AF: 0.306 AC: 0.30554 AN: 0.30554

Gnomad4 EAS AF: 0.0299 AC: 0.0299459 AN: 0.0299459

Gnomad4 SAS AF: 0.280 AC: 0.279601 AN: 0.279601

Gnomad4 FIN AF: 0.331 AC: 0.330619 AN: 0.330619

Gnomad4 NFE AF: 0.359 AC: 0.358524 AN: 0.358524

Gnomad4 OTH AF: 0.374 AC: 0.37358 AN: 0.37358

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.1
DANN	Benign	0.30
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

Publications

LitVar

Other links and lift over

dbSNP: rs6075193; hg19: chr20-17320057;