chr20-17465559-TG-T

Position:

• chr20-17465559-TG-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_002594.5(PCSK2):​c.1430+11del variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,543,892 control chromosomes in the GnomAD database, including 180 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (95 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (85 hom.)
• Consequence: PCSK2 NM_002594.5 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.07

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 -10 ACMG points.

• BP6: Variant 20-17465559-TG-T is Benign according to our data. Variant chr20-17465559-TG-T is described in ClinVar as [Benign]. Clinvar id is 777519.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK2	NM_002594.5	c.1430+11del		splice_region_variant, intron_variant		ENST00000262545.7
PCSK2	NM_001201528.2	c.1373+11del		splice_region_variant, intron_variant
PCSK2	NM_001201529.3	c.1325+11del		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK2	ENST00000262545.7	c.1430+11del		splice_region_variant, intron_variant		1	NM_002594.5	P1
PCSK2	ENST00000377899.5	c.1373+11del		splice_region_variant, intron_variant		1
PCSK2	ENST00000536609.1	c.1325+11del		splice_region_variant, intron_variant		2
PCSK2	ENST00000459871.1	n.2121+11del		splice_region_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2859 AN: 152162 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.0654

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00549 AC: 1176 AN: 214050 Hom.: 41 AF XY: 0.00374 AC XY: 426 AN XY: 113762

Gnomad AFR exome AF: 0.0671

Gnomad AMR exome AF: 0.00368

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000452

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.00332

GnomAD4 exome AF: 0.00191 AC: 2652 AN: 1391612 Hom.: 85 Cov.: 24 AF XY: 0.00160 AC XY: 1102 AN XY: 687258

Gnomad4 AFR exome AF: 0.0628

Gnomad4 AMR exome AF: 0.00419

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000511

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000202

Gnomad4 OTH exome AF: 0.00415

GnomAD4 genome AF: 0.0188 AC: 2866 AN: 152280 Hom.: 95 Cov.: 32 AF XY: 0.0174 AC XY: 1297 AN XY: 74464

Gnomad4 AFR AF: 0.0654

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0105 Hom.: 8

Bravo AF: 0.0213

Asia WGS AF: 0.00318 AC: 11 AN: 3478

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

Jun 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs140522302; hg19: chr20-17446204;