chr20-17374022-C-T

Variant names:

• chr20-17374022-C-T
• rs6080665
• NM_002594.5:c.543+4745C>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.543+4745C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 152,098 control chromosomes in the GnomAD database, including 6,425 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 (6425 hom., cov: 32)
• Consequence: PCSK2 NM_002594.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.113
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.46 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.543+4745C>T		intron	N/A	NP_002585.2
	PCSK2	NM_001201528.2		c.486+4745C>T		intron	N/A	NP_001188457.1	P16519-3
	PCSK2	NM_001201529.3		c.438+4745C>T		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.543+4745C>T		intron	N/A	ENSP00000262545.2	P16519-1
	PCSK2	ENST00000377899.5	TSL:1	c.486+4745C>T		intron	N/A	ENSP00000367131.1	P16519-3
	PCSK2	ENST00000947703.1		c.543+4745C>T		intron	N/A	ENSP00000617762.1

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39370 AN: 151978 Hom.: 6424 Cov.: 32

Gnomad AFR AF: 0.0601

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.287

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

GnomAD4 genome AF: 0.259 AC: 39361 AN: 152098 Hom.: 6425 Cov.: 32 AF XY: 0.262 AC XY: 19474 AN XY: 74338

African (AFR) AF: 0.0600 AC: 2488 AN: 41500

American (AMR) AF: 0.235 AC: 3593 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1066 AN: 3472

East Asian (EAS) AF: 0.274 AC: 1417 AN: 5166

South Asian (SAS) AF: 0.476 AC: 2298 AN: 4828

European-Finnish (FIN) AF: 0.317 AC: 3351 AN: 10556

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.356 AC: 24191 AN: 67974

Other (OTH) AF: 0.283 AC: 598 AN: 2116

Alfa AF: 0.306 Hom.: 4521

Bravo AF: 0.240

Asia WGS AF: 0.326 AC: 1133 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.93
DANN	Benign	0.70
PhyloP100		-0.11
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: rs6080665; hg19: chr20-17354667;