chr20-17376928-G-A

Variant names:

• chr20-17376928-G-A
• rs4814615
• NM_002594.5:c.543+7651G>A

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+7651G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 152,056 control chromosomes in the GnomAD database, including 4,021 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 0.22 (4021 hom., cov: 33)
• Consequence: PCSK2 NM_002594.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0200
• Publications: 19 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.483 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+7651G>A		intron	N/A	NP_002585.2
	PCSK2	NM_001201528.2		c.486+7651G>A		intron	N/A	NP_001188457.1
	PCSK2	NM_001201529.3		c.438+7651G>A		intron	N/A	NP_001188458.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK2	ENST00000262545.7	TSL:1 MANE Select	c.543+7651G>A		intron	N/A	ENSP00000262545.2
	PCSK2	ENST00000377899.5	TSL:1	c.486+7651G>A		intron	N/A	ENSP00000367131.1
	PCSK2	ENST00000947703.1		c.543+7651G>A		intron	N/A	ENSP00000617762.1

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32758 AN: 151938 Hom.: 4008 Cov.: 33

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.500

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.195

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

GnomAD4 genome AF: 0.216 AC: 32796 AN: 152056 Hom.: 4021 Cov.: 33 AF XY: 0.220 AC XY: 16326 AN XY: 74316

African (AFR) AF: 0.192 AC: 7976 AN: 41472

American (AMR) AF: 0.328 AC: 5009 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 655 AN: 3470

East Asian (EAS) AF: 0.499 AC: 2573 AN: 5154

South Asian (SAS) AF: 0.165 AC: 793 AN: 4820

European-Finnish (FIN) AF: 0.288 AC: 3043 AN: 10562

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.179 AC: 12145 AN: 67988

Other (OTH) AF: 0.199 AC: 421 AN: 2112

Alfa AF: 0.200 Hom.: 7664

Bravo AF: 0.225

Asia WGS AF: 0.332 AC: 1153 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.6
DANN	Benign	0.70
PhyloP100		0.020
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: rs4814615; hg19: chr20-17357573; COSMIC: COSV52741723;