20-17481830-G-A

Variant names:

• chr20-17481830-G-A
• rs11907317
• NM_002594.5:c.1677G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_002594.5(PCSK2):​c.1677G>A​(p.Thr559Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000807 in 1,614,138 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0039 (5 hom., cov: 30)
  • Exomes 𝑓: 0.00048 (2 hom.)
• Consequence: PCSK2 NM_002594.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.59
• Publications: 1 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 20-17481830-G-A is Benign according to our data. Variant chr20-17481830-G-A is described in ClinVar as Benign. ClinVar VariationId is 714814.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.6 with no splicing effect.
• BS2: High AC in GnomAd4 at 594 AD gene.

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.1677G>A	p.Thr559Thr	synonymous	Exon 12 of 12	NP_002585.2
	PCSK2	NM_001201528.2		c.1620G>A	p.Thr540Thr	synonymous	Exon 13 of 13	NP_001188457.1	P16519-3
	PCSK2	NM_001201529.3		c.1572G>A	p.Thr524Thr	synonymous	Exon 11 of 11	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.1677G>A	p.Thr559Thr	synonymous	Exon 12 of 12	ENSP00000262545.2	P16519-1
	PCSK2	ENST00000377899.5	TSL:1	c.1620G>A	p.Thr540Thr	synonymous	Exon 13 of 13	ENSP00000367131.1	P16519-3
	PCSK2	ENST00000947703.1		c.1674G>A	p.Thr558Thr	synonymous	Exon 12 of 12	ENSP00000617762.1

Frequencies

GnomAD3 genomes AF: 0.00388 AC: 591 AN: 152132 Hom.: 5 Cov.: 30

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00100 AC: 252 AN: 251280 AF XY: 0.000810

Gnomad AFR exome AF: 0.0135

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000484 AC: 708 AN: 1461888 Hom.: 2 Cov.: 32 AF XY: 0.000441 AC XY: 321 AN XY: 727246

African (AFR) AF: 0.0137 AC: 459 AN: 33480

American (AMR) AF: 0.000537 AC: 24 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.000134 AC: 149 AN: 1112012

Other (OTH) AF: 0.000993 AC: 60 AN: 60394

GnomAD4 genome AF: 0.00390 AC: 594 AN: 152250 Hom.: 5 Cov.: 30 AF XY: 0.00387 AC XY: 288 AN XY: 74440

African (AFR) AF: 0.0137 AC: 569 AN: 41548

American (AMR) AF: 0.000980 AC: 15 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68000

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00181 Hom.: 1

Bravo AF: 0.00434

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.4
DANN	Benign	0.87
PhyloP100		-1.6
Mutation Taster		=98/2	polymorphism

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: rs11907317; hg19: chr20-17462475; COSMIC: COSV99359171; COSMIC: COSV99359171;