rs6075209

Variant names:

• chr20-17434574-G-A
• rs6075209
• NM_002594.5:c.710-2134G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-17434574-G-A
• chr20-17434574-G-T

Variant summary

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

The NM_002594.5(PCSK2):​c.710-2134G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 151,992 control chromosomes in the GnomAD database, including 9,930 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 0.35 (9930 hom., cov: 31)
• Consequence: PCSK2 NM_002594.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.237
• Publications: 2 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=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.555 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.710-2134G>A		intron	N/A	NP_002585.2
	PCSK2	NM_001201528.2		c.653-2134G>A		intron	N/A	NP_001188457.1
	PCSK2	NM_001201529.3		c.605-2134G>A		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.710-2134G>A		intron	N/A	ENSP00000262545.2
	PCSK2	ENST00000377899.5	TSL:1	c.653-2134G>A		intron	N/A	ENSP00000367131.1
	PCSK2	ENST00000536609.1	TSL:2	c.605-2134G>A		intron	N/A	ENSP00000437458.1

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53568 AN: 151874 Hom.: 9930 Cov.: 31

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.411

Gnomad AMR AF: 0.299

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.573

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.385

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

GnomAD4 genome AF: 0.353 AC: 53583 AN: 151992 Hom.: 9930 Cov.: 31 AF XY: 0.355 AC XY: 26367 AN XY: 74272

African (AFR) AF: 0.255 AC: 10556 AN: 41436

American (AMR) AF: 0.298 AC: 4564 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 1235 AN: 3470

East Asian (EAS) AF: 0.304 AC: 1573 AN: 5170

South Asian (SAS) AF: 0.572 AC: 2745 AN: 4796

European-Finnish (FIN) AF: 0.360 AC: 3794 AN: 10544

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.409 AC: 27827 AN: 67978

Other (OTH) AF: 0.382 AC: 804 AN: 2104

Alfa AF: 0.380 Hom.: 14022

Bravo AF: 0.337

Asia WGS AF: 0.394 AC: 1370 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.4
DANN	Benign	0.73
PhyloP100		0.24
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: rs6075209; hg19: chr20-17415219;