20-17481830-G-A

Position:

• chr20-17481830-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_002594.5(PCSK2):​c.1677G>A​(p.Thr559=) 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

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

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK2	NM_002594.5	c.1677G>A	p.Thr559=	synonymous_variant	12/12	ENST00000262545.7	NP_002585.2
PCSK2	NM_001201528.2	c.1620G>A	p.Thr540=	synonymous_variant	13/13		NP_001188457.1
PCSK2	NM_001201529.3	c.1572G>A	p.Thr524=	synonymous_variant	11/11		NP_001188458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK2	ENST00000262545.7	c.1677G>A	p.Thr559=	synonymous_variant	12/12	1	NM_002594.5	ENSP00000262545	P1
PCSK2	ENST00000377899.5	c.1620G>A	p.Thr540=	synonymous_variant	13/13	1		ENSP00000367131
PCSK2	ENST00000536609.1	c.1572G>A	p.Thr524=	synonymous_variant	11/11	2		ENSP00000437458
PCSK2	ENST00000459871.1	n.2368G>A		non_coding_transcript_exon_variant	2/2	2

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

GnomAD3 exomes AF: 0.00100 AC: 252 AN: 251280 Hom.: 1 AF XY: 0.000810 AC XY: 110 AN XY: 135842

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 SAS exome AF: 0.0000653

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

Gnomad4 AFR exome AF: 0.0137

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000134

Gnomad4 OTH exome AF: 0.000993

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

Gnomad4 AFR AF: 0.0137

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00190 Hom.: 1

Bravo AF: 0.00434

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.4
DANN	Benign	0.87

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

Publications

LitVar

Other links and lift over

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