20-17343358-C-T

Position:

• chr20-17343358-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002594.5(PCSK2):​c.283-14969C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.921 in 152,228 control chromosomes in the GnomAD database, including 64,637 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 0.92 (64637 hom., cov: 32)
• Consequence: PCSK2 NM_002594.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.263

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.943 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK2	NM_002594.5	c.283-14969C>T		intron_variant		ENST00000262545.7
PCSK2	NM_001201528.2	c.226-14969C>T		intron_variant
PCSK2	NM_001201529.3	c.178-14969C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK2	ENST00000262545.7	c.283-14969C>T		intron_variant		1	NM_002594.5	P1
PCSK2	ENST00000377899.5	c.226-14969C>T		intron_variant		1
PCSK2	ENST00000536609.1	c.178-14969C>T		intron_variant		2
PCSK2	ENST00000470007.1	n.278-14969C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.921 AC: 140059 AN: 152110 Hom.: 64575 Cov.: 32

Gnomad AFR AF: 0.889

Gnomad AMI AF: 0.986

Gnomad AMR AF: 0.956

Gnomad ASJ AF: 0.915

Gnomad EAS AF: 0.814

Gnomad SAS AF: 0.956

Gnomad FIN AF: 0.883

Gnomad MID AF: 0.959

Gnomad NFE AF: 0.943

Gnomad OTH AF: 0.934

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

GnomAD4 genome AF: 0.921 AC: 140180 AN: 152228 Hom.: 64637 Cov.: 32 AF XY: 0.920 AC XY: 68440 AN XY: 74408

Gnomad4 AFR AF: 0.890

Gnomad4 AMR AF: 0.956

Gnomad4 ASJ AF: 0.915

Gnomad4 EAS AF: 0.813

Gnomad4 SAS AF: 0.957

Gnomad4 FIN AF: 0.883

Gnomad4 NFE AF: 0.943

Gnomad4 OTH AF: 0.933

Alfa AF: 0.936 Hom.: 39016

Bravo AF: 0.923

Asia WGS AF: 0.915 AC: 3181 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.5
DANN	Benign	0.78

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: rs2208203; hg19: chr20-17324003;