chr20-17441418-T-C

Variant names:

• chr20-17441418-T-C
• rs2021785
• NM_002594.5:c.885+4535T>C

Variant summary

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

The NM_002594.5(PCSK2):​c.885+4535T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.664 in 152,138 control chromosomes in the GnomAD database, including 33,894 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 0.66 (33894 hom., cov: 32)
• Consequence: PCSK2 NM_002594.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.121
• Publications: 8 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.746 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.885+4535T>C		intron	N/A	NP_002585.2
	PCSK2	NM_001201528.2		c.828+4535T>C		intron	N/A	NP_001188457.1
	PCSK2	NM_001201529.3		c.780+4535T>C		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.885+4535T>C		intron	N/A	ENSP00000262545.2
	PCSK2	ENST00000377899.5	TSL:1	c.828+4535T>C		intron	N/A	ENSP00000367131.1
	PCSK2	ENST00000536609.1	TSL:2	c.780+4535T>C		intron	N/A	ENSP00000437458.1

Frequencies

GnomAD3 genomes AF: 0.664 AC: 100948 AN: 152020 Hom.: 33869 Cov.: 32

Gnomad AFR AF: 0.753

Gnomad AMI AF: 0.525

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.578

Gnomad EAS AF: 0.662

Gnomad SAS AF: 0.736

Gnomad FIN AF: 0.584

Gnomad MID AF: 0.637

Gnomad NFE AF: 0.648

Gnomad OTH AF: 0.672

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

GnomAD4 genome AF: 0.664 AC: 101017 AN: 152138 Hom.: 33894 Cov.: 32 AF XY: 0.665 AC XY: 49440 AN XY: 74346

African (AFR) AF: 0.753 AC: 31247 AN: 41504

American (AMR) AF: 0.554 AC: 8472 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.578 AC: 2008 AN: 3472

East Asian (EAS) AF: 0.663 AC: 3427 AN: 5168

South Asian (SAS) AF: 0.735 AC: 3547 AN: 4828

European-Finnish (FIN) AF: 0.584 AC: 6163 AN: 10558

Middle Eastern (MID) AF: 0.637 AC: 186 AN: 292

European-Non Finnish (NFE) AF: 0.648 AC: 44074 AN: 67998

Other (OTH) AF: 0.670 AC: 1414 AN: 2110

Alfa AF: 0.652 Hom.: 22338

Bravo AF: 0.658

Asia WGS AF: 0.670 AC: 2327 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	7.0
DANN	Benign	0.69
PhyloP100		0.12
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: rs2021785; hg19: chr20-17422063;