rs1609659

Variant names:

• chr20-17242090-G-A
• rs1609659
• NM_002594.5:c.177+14608G>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.177+14608G>A 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 152,048 control chromosomes in the GnomAD database, including 15,260 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 (15260 hom., cov: 32)
• Consequence: PCSK2 NM_002594.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.665
• 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]

LOC105372546 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK2	NM_002594.5	c.177+14608G>A		intron_variant	Intron 1 of 11	ENST00000262545.7	NP_002585.2
PCSK2	NM_001201528.2	c.120+14608G>A		intron_variant	Intron 2 of 12		NP_001188457.1
PCSK2	NM_001201529.3	c.177+14608G>A		intron_variant	Intron 1 of 10		NP_001188458.1
LOC105372546	XR_007067540.1	n.254-9522C>T		intron_variant	Intron 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK2	ENST00000262545.7	c.177+14608G>A		intron_variant	Intron 1 of 11	1	NM_002594.5	ENSP00000262545.2
PCSK2	ENST00000377899.5	c.120+14608G>A		intron_variant	Intron 2 of 12	1		ENSP00000367131.1
PCSK2	ENST00000536609.1	c.177+14608G>A		intron_variant	Intron 1 of 10	2		ENSP00000437458.1
PCSK2	ENST00000470007.1	n.172+13788G>A		intron_variant	Intron 1 of 5	3

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66389 AN: 151930 Hom.: 15243 Cov.: 32

Gnomad AFR AF: 0.580

Gnomad AMI AF: 0.290

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.415

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.434

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

GnomAD4 genome AF: 0.437 AC: 66444 AN: 152048 Hom.: 15260 Cov.: 32 AF XY: 0.435 AC XY: 32330 AN XY: 74350

African (AFR) AF: 0.581 AC: 24068 AN: 41458

American (AMR) AF: 0.401 AC: 6120 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 1475 AN: 3468

East Asian (EAS) AF: 0.158 AC: 817 AN: 5162

South Asian (SAS) AF: 0.287 AC: 1385 AN: 4826

European-Finnish (FIN) AF: 0.415 AC: 4396 AN: 10584

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.395 AC: 26870 AN: 67962

Other (OTH) AF: 0.429 AC: 904 AN: 2108

Alfa AF: 0.424 Hom.: 2120

Bravo AF: 0.446

Asia WGS AF: 0.265 AC: 925 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.48
DANN	Benign	0.23
PhyloP100		-0.67
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: rs1609659; hg19: chr20-17222735;