rs727472

Variant names:

• chr20-17331428-A-T
• rs727472
• NM_002594.5:c.283-26899A>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.283-26899A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 152,008 control chromosomes in the GnomAD database, including 16,083 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 0.44 (16083 hom., cov: 32)
• Consequence: PCSK2 NM_002594.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.996
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.541 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.283-26899A>T		intron	N/A	NP_002585.2
	PCSK2	NM_001201528.2		c.226-26899A>T		intron	N/A	NP_001188457.1	P16519-3
	PCSK2	NM_001201529.3		c.178-26899A>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.283-26899A>T		intron	N/A	ENSP00000262545.2	P16519-1
	PCSK2	ENST00000377899.5	TSL:1	c.226-26899A>T		intron	N/A	ENSP00000367131.1	P16519-3
	PCSK2	ENST00000947703.1		c.283-26899A>T		intron	N/A	ENSP00000617762.1

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66381 AN: 151890 Hom.: 16087 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.801

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.475

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.522

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.546

Gnomad OTH AF: 0.459

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

GnomAD4 genome AF: 0.437 AC: 66389 AN: 152008 Hom.: 16083 Cov.: 32 AF XY: 0.437 AC XY: 32474 AN XY: 74312

African (AFR) AF: 0.245 AC: 10173 AN: 41458

American (AMR) AF: 0.415 AC: 6337 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 1646 AN: 3468

East Asian (EAS) AF: 0.224 AC: 1157 AN: 5176

South Asian (SAS) AF: 0.548 AC: 2640 AN: 4816

European-Finnish (FIN) AF: 0.522 AC: 5503 AN: 10548

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.546 AC: 37099 AN: 67954

Other (OTH) AF: 0.456 AC: 959 AN: 2104

Alfa AF: 0.479 Hom.: 2268

Bravo AF: 0.420

Asia WGS AF: 0.389 AC: 1354 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.7
DANN	Benign	0.71
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs727472; hg19: chr20-17312073;