chr15-101365954-T-A

Position:

• chr15-101365954-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000611716.5(PCSK6):​c.1858+242A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 356,284 control chromosomes in the GnomAD database, including 28,071 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 0.40 (13636 hom., cov: 32)
  • Exomes 𝑓: 0.36 (14435 hom.)
• Consequence: PCSK6 ENST00000611716.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.31

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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK6	NM_002570.5	c.1858+242A>T		intron_variant		ENST00000611716.5	NP_002561.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK6	ENST00000611716.5	c.1858+242A>T		intron_variant		1	NM_002570.5	ENSP00000482760	A2

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61202 AN: 151860 Hom.: 13603 Cov.: 32

Gnomad AFR AF: 0.559

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.511

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.577

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.376

GnomAD4 exome AF: 0.357 AC: 72999 AN: 204306 Hom.: 14435 Cov.: 4 AF XY: 0.351 AC XY: 36786 AN XY: 104856

Gnomad4 AFR exome AF: 0.568

Gnomad4 AMR exome AF: 0.577

Gnomad4 ASJ exome AF: 0.288

Gnomad4 EAS exome AF: 0.602

Gnomad4 SAS exome AF: 0.190

Gnomad4 FIN exome AF: 0.322

Gnomad4 NFE exome AF: 0.328

Gnomad4 OTH exome AF: 0.364

GnomAD4 genome AF: 0.403 AC: 61295 AN: 151978 Hom.: 13636 Cov.: 32 AF XY: 0.400 AC XY: 29714 AN XY: 74264

Gnomad4 AFR AF: 0.559

Gnomad4 AMR AF: 0.512

Gnomad4 ASJ AF: 0.278

Gnomad4 EAS AF: 0.577

Gnomad4 SAS AF: 0.181

Gnomad4 FIN AF: 0.296

Gnomad4 NFE AF: 0.313

Gnomad4 OTH AF: 0.373

Alfa AF: 0.346 Hom.: 1216

Bravo AF: 0.439

Asia WGS AF: 0.358 AC: 1249 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.10
DANN	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs8029797; hg19: chr15-101906159;