15-101499466-G-C

Variant names:

• chr15-101499466-G-C
• rs8033863
• ENST00000557794.5:n.123+25614C>G

Variant summary

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

The ENST00000557794.5(PCSK6):​n.123+25614C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 151,872 control chromosomes in the GnomAD database, including 10,380 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 0.37 (10380 hom., cov: 31)
• Consequence: PCSK6 ENST00000557794.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.363
• Publications: 3 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.46 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+25614C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.369 AC: 55935 AN: 151754 Hom.: 10379 Cov.: 31

Gnomad AFR AF: 0.353

Gnomad AMI AF: 0.484

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.368

Gnomad OTH AF: 0.372

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

GnomAD4 genome AF: 0.369 AC: 55965 AN: 151872 Hom.: 10380 Cov.: 31 AF XY: 0.367 AC XY: 27252 AN XY: 74246

African (AFR) AF: 0.353 AC: 14584 AN: 41350

American (AMR) AF: 0.423 AC: 6469 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1056 AN: 3470

East Asian (EAS) AF: 0.475 AC: 2452 AN: 5158

South Asian (SAS) AF: 0.381 AC: 1831 AN: 4806

European-Finnish (FIN) AF: 0.306 AC: 3232 AN: 10566

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.368 AC: 25010 AN: 67924

Other (OTH) AF: 0.370 AC: 782 AN: 2112

Alfa AF: 0.221 Hom.: 508

Bravo AF: 0.379

Asia WGS AF: 0.385 AC: 1340 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.4
DANN	Benign	0.80
PhyloP100		0.36

Splicing

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

Other links and lift over

dbSNP: rs8033863; hg19: chr15-102039669;