15-101347562-C-T

Variant names:

• chr15-101347562-C-T
• rs2949
• ENST00000611967.4:c.*161G>A

Variant summary

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

The ENST00000611967.4(PCSK6):​c.*161G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.512 in 1,414,002 control chromosomes in the GnomAD database, including 188,434 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 (16884 hom., cov: 34)
  • Exomes 𝑓: 0.52 (171550 hom.)
• Consequence: PCSK6 ENST00000611967.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.787
• Publications: 12 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK6	NM_002570.5	c.1859-15531G>A		intron_variant	Intron 13 of 21	ENST00000611716.5	NP_002561.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK6	ENST00000611716.5	c.1859-15531G>A		intron_variant	Intron 13 of 21	1	NM_002570.5	ENSP00000482760.1

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69592 AN: 152028 Hom.: 16882 Cov.: 34

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.571

Gnomad AMR AF: 0.578

Gnomad ASJ AF: 0.400

Gnomad EAS AF: 0.640

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.486

GnomAD4 exome AF: 0.518 AC: 654161 AN: 1261856 Hom.: 171550 Cov.: 35 AF XY: 0.518 AC XY: 315439 AN XY: 609110

African (AFR) AF: 0.281 AC: 7924 AN: 28234

American (AMR) AF: 0.598 AC: 12973 AN: 21688

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 7462 AN: 18272

East Asian (EAS) AF: 0.641 AC: 22280 AN: 34768

South Asian (SAS) AF: 0.466 AC: 25814 AN: 55382

European-Finnish (FIN) AF: 0.464 AC: 17910 AN: 38612

Middle Eastern (MID) AF: 0.529 AC: 1895 AN: 3580

European-Non Finnish (NFE) AF: 0.527 AC: 531541 AN: 1009318

Other (OTH) AF: 0.507 AC: 26362 AN: 52002

GnomAD4 genome AF: 0.458 AC: 69620 AN: 152146 Hom.: 16884 Cov.: 34 AF XY: 0.456 AC XY: 33895 AN XY: 74388

African (AFR) AF: 0.291 AC: 12100 AN: 41512

American (AMR) AF: 0.578 AC: 8845 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 1388 AN: 3470

East Asian (EAS) AF: 0.641 AC: 3317 AN: 5178

South Asian (SAS) AF: 0.466 AC: 2248 AN: 4820

European-Finnish (FIN) AF: 0.441 AC: 4667 AN: 10574

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.520 AC: 35379 AN: 67984

Other (OTH) AF: 0.481 AC: 1017 AN: 2114

Alfa AF: 0.497 Hom.: 37283

Bravo AF: 0.466

Asia WGS AF: 0.503 AC: 1750 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	0.23
DANN	Benign	0.55
PhyloP100		-0.79
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2949; hg19: chr15-101887767;