15-101478640-G-T

Variant names:

• chr15-101478640-G-T
• rs7174882
• NM_002570.5:c.297+10734C>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.297+10734C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 151,982 control chromosomes in the GnomAD database, including 23,275 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 0.54 (23275 hom., cov: 32)
• Consequence: PCSK6 NM_002570.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.950
• 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

LOC124903566 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.813 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.297+10734C>A		intron	N/A	NP_002561.1	P29122-1
	PCSK6	NM_138319.4		c.297+10734C>A		intron	N/A	NP_612192.1	P29122-2
	PCSK6	NM_001291309.2		c.297+10734C>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.297+10734C>A		intron	N/A	ENSP00000482760.1	P29122-1
	PCSK6	ENST00000622483.4	TSL:1	c.297+10734C>A		intron	N/A	ENSP00000481556.1	A0A087WY68
	PCSK6	ENST00000619160.4	TSL:1	c.297+10734C>A		intron	N/A	ENSP00000482831.1	A0A087WZR0

Frequencies

GnomAD3 genomes AF: 0.545 AC: 82703 AN: 151864 Hom.: 23234 Cov.: 32

Gnomad AFR AF: 0.544

Gnomad AMI AF: 0.678

Gnomad AMR AF: 0.696

Gnomad ASJ AF: 0.620

Gnomad EAS AF: 0.835

Gnomad SAS AF: 0.632

Gnomad FIN AF: 0.416

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.496

Gnomad OTH AF: 0.578

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

GnomAD4 genome AF: 0.545 AC: 82794 AN: 151982 Hom.: 23275 Cov.: 32 AF XY: 0.547 AC XY: 40607 AN XY: 74288

African (AFR) AF: 0.545 AC: 22546 AN: 41398

American (AMR) AF: 0.697 AC: 10652 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.620 AC: 2150 AN: 3470

East Asian (EAS) AF: 0.834 AC: 4300 AN: 5154

South Asian (SAS) AF: 0.632 AC: 3045 AN: 4820

European-Finnish (FIN) AF: 0.416 AC: 4394 AN: 10564

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.496 AC: 33709 AN: 67974

Other (OTH) AF: 0.583 AC: 1231 AN: 2112

Alfa AF: 0.515 Hom.: 10402

Bravo AF: 0.570

Asia WGS AF: 0.743 AC: 2584 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.16
DANN	Benign	0.48
PhyloP100		-0.95
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: rs7174882; hg19: chr15-102018845;