rs6080699

Variant names:

• chr20-17453641-G-C
• rs6080699
• NM_002594.5:c.886-101G>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.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
• Publications: 3 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=-0.84).
• 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 rank	MANE	Protein	UniProt
PCSK2	NM_002594.5	c.886-101G>C		intron_variant	Intron 8 of 11	ENST00000262545.7	NP_002585.2
PCSK2	NM_001201528.2	c.829-101G>C		intron_variant	Intron 9 of 12		NP_001188457.1
PCSK2	NM_001201529.3	c.781-101G>C		intron_variant	Intron 7 of 10		NP_001188458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK2	ENST00000262545.7	c.886-101G>C		intron_variant	Intron 8 of 11	1	NM_002594.5	ENSP00000262545.2
PCSK2	ENST00000377899.5	c.829-101G>C		intron_variant	Intron 9 of 12	1		ENSP00000367131.1
PCSK2	ENST00000536609.1	c.781-101G>C		intron_variant	Intron 7 of 10	2		ENSP00000437458.1

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

African (AFR) AF: 0.0535 AC: 1438 AN: 26870

American (AMR) AF: 0.248 AC: 8630 AN: 34798

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 5462 AN: 21568

East Asian (EAS) AF: 0.289 AC: 10605 AN: 36654

South Asian (SAS) AF: 0.485 AC: 35128 AN: 72414

European-Finnish (FIN) AF: 0.327 AC: 11961 AN: 36546

Middle Eastern (MID) AF: 0.279 AC: 1049 AN: 3758

European-Non Finnish (NFE) AF: 0.358 AC: 305359 AN: 853014

Other (OTH) AF: 0.328 AC: 16025 AN: 48898

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

African (AFR) AF: 0.0594 AC: 2466 AN: 41544

American (AMR) AF: 0.257 AC: 3935 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 904 AN: 3468

East Asian (EAS) AF: 0.301 AC: 1557 AN: 5172

South Asian (SAS) AF: 0.475 AC: 2292 AN: 4826

European-Finnish (FIN) AF: 0.322 AC: 3407 AN: 10580

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.355 AC: 24128 AN: 67962

Other (OTH) AF: 0.291 AC: 615 AN: 2112

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
PhyloP100		-0.98
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: rs6080699; hg19: chr20-17434286; COSMIC: COSV52742712;