rs1006273

Variant names:

• chr15-101425134-T-A
• rs1006273
• NM_002570.5:c.823+2758A>T

Variant summary

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

The NM_002570.5(PCSK6):​c.823+2758A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 151,782 control chromosomes in the GnomAD database, including 16,134 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 0.46 (16134 hom., cov: 31)
• Consequence: PCSK6 NM_002570.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0460
• Publications: 0 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK6	NM_002570.5	c.823+2758A>T		intron_variant	Intron 6 of 21	ENST00000611716.5	NP_002561.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK6	ENST00000611716.5	c.823+2758A>T		intron_variant	Intron 6 of 21	1	NM_002570.5	ENSP00000482760.1

Frequencies

GnomAD3 genomes AF: 0.456 AC: 69208 AN: 151664 Hom.: 16112 Cov.: 31

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.462

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.456

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.422

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

GnomAD4 genome AF: 0.456 AC: 69270 AN: 151782 Hom.: 16134 Cov.: 31 AF XY: 0.450 AC XY: 33407 AN XY: 74174

African (AFR) AF: 0.526 AC: 21781 AN: 41374

American (AMR) AF: 0.358 AC: 5460 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 1602 AN: 3468

East Asian (EAS) AF: 0.292 AC: 1504 AN: 5142

South Asian (SAS) AF: 0.284 AC: 1364 AN: 4800

European-Finnish (FIN) AF: 0.456 AC: 4795 AN: 10526

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.461 AC: 31298 AN: 67912

Other (OTH) AF: 0.418 AC: 879 AN: 2104

Alfa AF: 0.473 Hom.: 2150

Bravo AF: 0.454

Asia WGS AF: 0.276 AC: 960 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.5
DANN	Benign	0.81
PhyloP100		0.046
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1006273; hg19: chr15-101965339;