20-17430198-T-C

Variant names:

• chr20-17430198-T-C
• rs6044808
• NM_002594.5:c.709+675T>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.709+675T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 151,860 control chromosomes in the GnomAD database, including 1,502 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 0.12 (1502 hom., cov: 32)
• Consequence: PCSK2 NM_002594.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0280
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.221 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK2	NM_002594.5	MANE Select	c.709+675T>C		intron	N/A	NP_002585.2
	PCSK2	NM_001201528.2		c.652+675T>C		intron	N/A	NP_001188457.1	P16519-3
	PCSK2	NM_001201529.3		c.604+675T>C		intron	N/A	NP_001188458.1	P16519-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK2	ENST00000262545.7	TSL:1 MANE Select	c.709+675T>C		intron	N/A	ENSP00000262545.2	P16519-1
	PCSK2	ENST00000377899.5	TSL:1	c.652+675T>C		intron	N/A	ENSP00000367131.1	P16519-3
	PCSK2	ENST00000947703.1		c.709+675T>C		intron	N/A	ENSP00000617762.1

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18685 AN: 151742 Hom.: 1500 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0443

Gnomad FIN AF: 0.0697

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.0842

Gnomad OTH AF: 0.123

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

GnomAD4 genome AF: 0.123 AC: 18698 AN: 151860 Hom.: 1502 Cov.: 32 AF XY: 0.121 AC XY: 8983 AN XY: 74230

African (AFR) AF: 0.225 AC: 9310 AN: 41352

American (AMR) AF: 0.104 AC: 1595 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 711 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5176

South Asian (SAS) AF: 0.0443 AC: 213 AN: 4808

European-Finnish (FIN) AF: 0.0697 AC: 734 AN: 10536

Middle Eastern (MID) AF: 0.240 AC: 70 AN: 292

European-Non Finnish (NFE) AF: 0.0842 AC: 5722 AN: 67950

Other (OTH) AF: 0.123 AC: 259 AN: 2102

Alfa AF: 0.0815 Hom.: 486

Bravo AF: 0.130

Asia WGS AF: 0.0620 AC: 217 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.9
DANN	Benign	0.82
PhyloP100		0.028
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: rs6044808; hg19: chr20-17410843;