rs6080699

Positions:

• chr20-17453641-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002594.5(PCSK2):​c.886-101G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,286,676 control chromosomes in the GnomAD database, including 78,789 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 0.26 (6489 hom., cov: 33)
  • Exomes 𝑓: 0.35 (72300 hom.)
• Consequence: PCSK2 NM_002594.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.977

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK2	NM_002594.5	c.886-101G>C		intron_variant		ENST00000262545.7
PCSK2	NM_001201528.2	c.829-101G>C		intron_variant
PCSK2	NM_001201529.3	c.781-101G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK2	ENST00000262545.7	c.886-101G>C		intron_variant		1	NM_002594.5	P1
PCSK2	ENST00000377899.5	c.829-101G>C		intron_variant		1
PCSK2	ENST00000536609.1	c.781-101G>C		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39694 AN: 152038 Hom.: 6492 Cov.: 33

Gnomad AFR AF: 0.0595

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.300

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.295

GnomAD4 exome AF: 0.349 AC: 395657 AN: 1134520 Hom.: 72300 AF XY: 0.354 AC XY: 201718 AN XY: 569658

Gnomad4 AFR exome AF: 0.0535

Gnomad4 AMR exome AF: 0.248

Gnomad4 ASJ exome AF: 0.253

Gnomad4 EAS exome AF: 0.289

Gnomad4 SAS exome AF: 0.485

Gnomad4 FIN exome AF: 0.327

Gnomad4 NFE exome AF: 0.358

Gnomad4 OTH exome AF: 0.328

GnomAD4 genome AF: 0.261 AC: 39678 AN: 152156 Hom.: 6489 Cov.: 33 AF XY: 0.264 AC XY: 19674 AN XY: 74382

Gnomad4 AFR AF: 0.0594

Gnomad4 AMR AF: 0.257

Gnomad4 ASJ AF: 0.261

Gnomad4 EAS AF: 0.301

Gnomad4 SAS AF: 0.475

Gnomad4 FIN AF: 0.322

Gnomad4 NFE AF: 0.355

Gnomad4 OTH AF: 0.291

Alfa AF: 0.312 Hom.: 1182

Bravo AF: 0.244

Asia WGS AF: 0.330 AC: 1147 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.34
DANN	Benign	0.73

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: rs6080699; hg19: chr20-17434286; COSMIC: COSV52742712;