rs2949

Positions:

• chr15-101347562-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 (EAS) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK6	NM_002570.5	c.1859-15531G>A		intron_variant		ENST00000611716.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK6	ENST00000611716.5	c.1859-15531G>A		intron_variant		1	NM_002570.5	A2

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

Gnomad4 AFR exome AF: 0.281

Gnomad4 AMR exome AF: 0.598

Gnomad4 ASJ exome AF: 0.408

Gnomad4 EAS exome AF: 0.641

Gnomad4 SAS exome AF: 0.466

Gnomad4 FIN exome AF: 0.464

Gnomad4 NFE exome AF: 0.527

Gnomad4 OTH exome AF: 0.507

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

Gnomad4 AFR AF: 0.291

Gnomad4 AMR AF: 0.578

Gnomad4 ASJ AF: 0.400

Gnomad4 EAS AF: 0.641

Gnomad4 SAS AF: 0.466

Gnomad4 FIN AF: 0.441

Gnomad4 NFE AF: 0.520

Gnomad4 OTH AF: 0.481

Alfa AF: 0.516 Hom.: 27280

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2949; hg19: chr15-101887767;