rs4814597

Variant names:

• chr20-17230988-A-G
• rs4814597
• NM_002594.5:c.177+3506A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002594.5(PCSK2):​c.177+3506A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 152,110 control chromosomes in the GnomAD database, including 15,861 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 (15861 hom., cov: 33)
• Consequence: PCSK2 NM_002594.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.838
• 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.597 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK2	NM_002594.5	MANE Select	c.177+3506A>G		intron	N/A	NP_002585.2
	PCSK2	NM_001201528.2		c.120+3506A>G		intron	N/A	NP_001188457.1
	PCSK2	NM_001201529.3		c.177+3506A>G		intron	N/A	NP_001188458.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK2	ENST00000262545.7	TSL:1 MANE Select	c.177+3506A>G		intron	N/A	ENSP00000262545.2
	PCSK2	ENST00000377899.5	TSL:1	c.120+3506A>G		intron	N/A	ENSP00000367131.1
	PCSK2	ENST00000536609.1	TSL:2	c.177+3506A>G		intron	N/A	ENSP00000437458.1

Frequencies

GnomAD3 genomes AF: 0.443 AC: 67404 AN: 151990 Hom.: 15843 Cov.: 33

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.290

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.414

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.441

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

GnomAD4 genome AF: 0.443 AC: 67458 AN: 152110 Hom.: 15861 Cov.: 33 AF XY: 0.441 AC XY: 32787 AN XY: 74346

African (AFR) AF: 0.603 AC: 25011 AN: 41494

American (AMR) AF: 0.404 AC: 6169 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 1476 AN: 3470

East Asian (EAS) AF: 0.160 AC: 832 AN: 5186

South Asian (SAS) AF: 0.287 AC: 1384 AN: 4826

European-Finnish (FIN) AF: 0.414 AC: 4373 AN: 10570

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

European-Non Finnish (NFE) AF: 0.396 AC: 26885 AN: 67964

Other (OTH) AF: 0.436 AC: 919 AN: 2110

Alfa AF: 0.421 Hom.: 1772

Bravo AF: 0.453

Asia WGS AF: 0.269 AC: 935 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.39
DANN	Benign	0.53
PhyloP100		-0.84
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: rs4814597; hg19: chr20-17211633;