rs714647

Positions:

• chr15-101512431-G-A

Variant summary

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

The ENST00000557794.5(PCSK6):​n.123+12649C>T variant causes a intron, non coding transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 151,584 control chromosomes in the GnomAD database, including 24,759 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 0.56 (24759 hom., cov: 31)
• Consequence: PCSK6 ENST00000557794.5 intron, non_coding_transcript
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0510

Genes affected

PCSK6 (HGNC:8569): (proprotein convertase subtilisin/kexin type 6) 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 encoded protein undergoes an initial autocatalytic processing event in the ER to generate a heterodimer which exits the ER and sorts to the trans-Golgi network where a second autocatalytic event takes place and the catalytic activity is acquired. The encoded protease is constitutively secreted into the extracellular matrix and expressed in many tissues, including neuroendocrine, liver, gut, and brain. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. Some of its substrates include transforming growth factor beta related proteins, proalbumin, and von Willebrand factor. This gene is thought to play a role in tumor progression and left-right patterning. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK6	ENST00000557794.5	n.123+12649C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.557 AC: 84401 AN: 151466 Hom.: 24748 Cov.: 31

Gnomad AFR AF: 0.358

Gnomad AMI AF: 0.704

Gnomad AMR AF: 0.692

Gnomad ASJ AF: 0.587

Gnomad EAS AF: 0.730

Gnomad SAS AF: 0.556

Gnomad FIN AF: 0.620

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.621

Gnomad OTH AF: 0.586

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

GnomAD4 genome AF: 0.557 AC: 84445 AN: 151584 Hom.: 24759 Cov.: 31 AF XY: 0.559 AC XY: 41359 AN XY: 74014

Gnomad4 AFR AF: 0.358

Gnomad4 AMR AF: 0.692

Gnomad4 ASJ AF: 0.587

Gnomad4 EAS AF: 0.729

Gnomad4 SAS AF: 0.556

Gnomad4 FIN AF: 0.620

Gnomad4 NFE AF: 0.621

Gnomad4 OTH AF: 0.585

Alfa AF: 0.607 Hom.: 38359

Bravo AF: 0.557

Asia WGS AF: 0.575 AC: 2000 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.8
DANN	Benign	0.57

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs714647; hg19: chr15-102052634;