rs714647

Variant names:

• chr15-101512431-G-A
• rs714647
• ENST00000557794.5:n.123+12649C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000557794.5(PCSK6):​n.123+12649C>T variant causes a intron 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0510
• Publications: 4 publications found

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]

PCSK6 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000557794.5. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK6	ENST00000557794.5	TSL:5	n.123+12649C>T		intron	N/A

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

African (AFR) AF: 0.358 AC: 14781 AN: 41294

American (AMR) AF: 0.692 AC: 10555 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.587 AC: 2039 AN: 3472

East Asian (EAS) AF: 0.729 AC: 3730 AN: 5114

South Asian (SAS) AF: 0.556 AC: 2671 AN: 4804

European-Finnish (FIN) AF: 0.620 AC: 6473 AN: 10436

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.621 AC: 42160 AN: 67912

Other (OTH) AF: 0.585 AC: 1231 AN: 2104

Alfa AF: 0.605 Hom.: 50233

Bravo AF: 0.557

Asia WGS AF: 0.575 AC: 2000 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.8
DANN	Benign	0.57
PhyloP100		0.051

Splicing

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

Other links and lift over

dbSNP: rs714647; hg19: chr15-102052634;