chr20-17452434-T-C

Variant names:

• chr20-17452434-T-C
• rs2269023
• NM_002594.5:c.886-1308T>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.886-1308T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 152,064 control chromosomes in the GnomAD database, including 25,638 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 0.58 (25638 hom., cov: 33)
• Consequence: PCSK2 NM_002594.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.423
• Publications: 9 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=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.694 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.886-1308T>C		intron	N/A	NP_002585.2
	PCSK2	NM_001201528.2		c.829-1308T>C		intron	N/A	NP_001188457.1	P16519-3
	PCSK2	NM_001201529.3		c.781-1308T>C		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.886-1308T>C		intron	N/A	ENSP00000262545.2	P16519-1
	PCSK2	ENST00000377899.5	TSL:1	c.829-1308T>C		intron	N/A	ENSP00000367131.1	P16519-3
	PCSK2	ENST00000947703.1		c.886-1308T>C		intron	N/A	ENSP00000617762.1

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87733 AN: 151946 Hom.: 25628 Cov.: 33

Gnomad AFR AF: 0.502

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.584

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.675

Gnomad SAS AF: 0.714

Gnomad FIN AF: 0.541

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.615

Gnomad OTH AF: 0.609

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

GnomAD4 genome AF: 0.577 AC: 87791 AN: 152064 Hom.: 25638 Cov.: 33 AF XY: 0.580 AC XY: 43121 AN XY: 74332

African (AFR) AF: 0.502 AC: 20814 AN: 41472

American (AMR) AF: 0.584 AC: 8927 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 1761 AN: 3472

East Asian (EAS) AF: 0.677 AC: 3494 AN: 5164

South Asian (SAS) AF: 0.714 AC: 3445 AN: 4824

European-Finnish (FIN) AF: 0.541 AC: 5717 AN: 10564

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

European-Non Finnish (NFE) AF: 0.615 AC: 41776 AN: 67960

Other (OTH) AF: 0.607 AC: 1281 AN: 2110

Alfa AF: 0.598 Hom.: 15431

Bravo AF: 0.572

Asia WGS AF: 0.642 AC: 2228 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.5
DANN	Benign	0.72
PhyloP100		-0.42
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: rs2269023; hg19: chr20-17433079;