15-101370529-G-C

Position:

• chr15-101370529-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002570.5(PCSK6):​c.1533-6C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,463,894 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (19 hom., cov: 34)
  • Exomes 𝑓: 0.00093 (21 hom.)
• Consequence: PCSK6 NM_002570.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0850

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 15-101370529-G-C is Benign according to our data. Variant chr15-101370529-G-C is described in ClinVar as [Benign]. Clinvar id is 790156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00892 (1359/152394) while in subpopulation AFR AF= 0.0301 (1254/41598). AF 95% confidence interval is 0.0288. There are 19 homozygotes in gnomad4. There are 631 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK6	NM_002570.5	c.1533-6C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000611716.5	NP_002561.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK6	ENST00000611716.5	c.1533-6C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002570.5	ENSP00000482760	A2

Frequencies

GnomAD3 genomes AF: 0.00892 AC: 1358 AN: 152276 Hom.: 19 Cov.: 34

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00240 AC: 226 AN: 94332 Hom.: 1 AF XY: 0.00213 AC XY: 104 AN XY: 48756

Gnomad AFR exome AF: 0.0305

Gnomad AMR exome AF: 0.00169

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000135

Gnomad SAS exome AF: 0.0000903

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00190

GnomAD4 exome AF: 0.000931 AC: 1221 AN: 1311500 Hom.: 21 Cov.: 33 AF XY: 0.000847 AC XY: 542 AN XY: 639744

Gnomad4 AFR exome AF: 0.0325

Gnomad4 AMR exome AF: 0.00191

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000210

Gnomad4 SAS exome AF: 0.0000900

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000882

Gnomad4 OTH exome AF: 0.00205

GnomAD4 genome AF: 0.00892 AC: 1359 AN: 152394 Hom.: 19 Cov.: 34 AF XY: 0.00847 AC XY: 631 AN XY: 74526

Gnomad4 AFR AF: 0.0301

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00483 Hom.: 2

Bravo AF: 0.00983

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.5
DANN	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs56087436; hg19: chr15-101910734;