rs4814615

Positions:

• chr20-17376928-G-A

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK2	NM_002594.5	c.543+7651G>A		intron_variant		ENST00000262545.7	NP_002585.2
PCSK2	NM_001201528.2	c.486+7651G>A		intron_variant			NP_001188457.1
PCSK2	NM_001201529.3	c.438+7651G>A		intron_variant			NP_001188458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK2	ENST00000262545.7	c.543+7651G>A		intron_variant		1	NM_002594.5	ENSP00000262545.2
PCSK2	ENST00000377899.5	c.486+7651G>A		intron_variant		1		ENSP00000367131.1
PCSK2	ENST00000536609.1	c.438+7651G>A		intron_variant		2		ENSP00000437458.1
PCSK2	ENST00000470007.1	n.538+7651G>A		intron_variant		3

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

Gnomad4 AFR AF: 0.192

Gnomad4 AMR AF: 0.328

Gnomad4 ASJ AF: 0.189

Gnomad4 EAS AF: 0.499

Gnomad4 SAS AF: 0.165

Gnomad4 FIN AF: 0.288

Gnomad4 NFE AF: 0.179

Gnomad4 OTH AF: 0.199

Alfa AF: 0.194 Hom.: 2162

Bravo AF: 0.225

Asia WGS AF: 0.332 AC: 1153 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.6
DANN	Benign	0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs4814615; hg19: chr20-17357573; COSMIC: COSV52741723;