rs7168655

Positions:

• chr15-101424716-G-A

Variant summary

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

The ENST00000611716.5(PCSK6):​c.823+3176C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 152,040 control chromosomes in the GnomAD database, including 10,370 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 0.36 (10370 hom., cov: 33)
• Consequence: PCSK6 ENST00000611716.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.701

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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK6	NM_002570.5	c.823+3176C>T		intron_variant		ENST00000611716.5	NP_002561.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK6	ENST00000611716.5	c.823+3176C>T		intron_variant		1	NM_002570.5	ENSP00000482760	A2

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54320 AN: 151922 Hom.: 10358 Cov.: 33

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.366

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.330

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.327

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

GnomAD4 genome AF: 0.358 AC: 54372 AN: 152040 Hom.: 10370 Cov.: 33 AF XY: 0.350 AC XY: 25996 AN XY: 74304

Gnomad4 AFR AF: 0.464

Gnomad4 AMR AF: 0.250

Gnomad4 ASJ AF: 0.366

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.330

Gnomad4 NFE AF: 0.354

Gnomad4 OTH AF: 0.325

Alfa AF: 0.346 Hom.: 18193

Bravo AF: 0.359

Asia WGS AF: 0.134 AC: 466 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.38
DANN	Benign	0.41

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: rs7168655; hg19: chr15-101964921;