15-101327282-C-T

Variant names:

• chr15-101327282-C-T
• rs1471656
• NM_002570.5:c.2078-803G>A

Variant summary

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

The NM_002570.5(PCSK6):​c.2078-803G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 151,948 control chromosomes in the GnomAD database, including 15,037 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 0.44 (15037 hom., cov: 32)
• Consequence: PCSK6 NM_002570.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.18
• 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.59 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002570.5. 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
	PCSK6	NM_002570.5	MANE Select	c.2078-803G>A		intron	N/A	NP_002561.1	P29122-1
	PCSK6	NM_138319.4		c.2039-803G>A		intron	N/A	NP_612192.1	P29122-2
	PCSK6	NM_001291309.2		c.1856-803G>A		intron	N/A	NP_001278238.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK6	ENST00000611716.5	TSL:1 MANE Select	c.2078-803G>A		intron	N/A	ENSP00000482760.1	P29122-1
	PCSK6	ENST00000622483.4	TSL:1	c.2078-803G>A		intron	N/A	ENSP00000481556.1	A0A087WY68
	PCSK6	ENST00000619160.4	TSL:1	c.2039-803G>A		intron	N/A	ENSP00000482831.1	A0A087WZR0

Frequencies

GnomAD3 genomes AF: 0.439 AC: 66618 AN: 151832 Hom.: 15016 Cov.: 32

Gnomad AFR AF: 0.368

Gnomad AMI AF: 0.659

Gnomad AMR AF: 0.600

Gnomad ASJ AF: 0.412

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.463

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

GnomAD4 genome AF: 0.439 AC: 66680 AN: 151948 Hom.: 15037 Cov.: 32 AF XY: 0.436 AC XY: 32344 AN XY: 74264

African (AFR) AF: 0.369 AC: 15263 AN: 41408

American (AMR) AF: 0.601 AC: 9176 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.412 AC: 1428 AN: 3462

East Asian (EAS) AF: 0.471 AC: 2430 AN: 5162

South Asian (SAS) AF: 0.352 AC: 1693 AN: 4812

European-Finnish (FIN) AF: 0.347 AC: 3667 AN: 10558

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.461 AC: 31317 AN: 67948

Other (OTH) AF: 0.460 AC: 973 AN: 2114

Alfa AF: 0.458 Hom.: 12454

Bravo AF: 0.461

Asia WGS AF: 0.396 AC: 1381 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.065
DANN	Benign	0.53
PhyloP100		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
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: rs1471656; hg19: chr15-101867487;