rs1871977

Positions:

• chr15-101322930-A-C
• chr15-101322930-A-T

Variant summary

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

The NM_002570.5(PCSK6):​c.2378-323T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.667 in 151,740 control chromosomes in the GnomAD database, including 34,058 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 0.67 (34058 hom., cov: 33)
• Consequence: PCSK6 NM_002570.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40

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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK6	NM_002570.5	c.2378-323T>G		intron_variant		ENST00000611716.5	NP_002561.1
PCSK6	NM_001291309.2	c.2156-323T>G		intron_variant			NP_001278238.1
PCSK6	NM_138319.4	c.2339-323T>G		intron_variant			NP_612192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK6	ENST00000611716.5	c.2378-323T>G		intron_variant		1	NM_002570.5	ENSP00000482760	A2

Frequencies

GnomAD3 genomes AF: 0.667 AC: 101094 AN: 151622 Hom.: 34019 Cov.: 33

Gnomad AFR AF: 0.711

Gnomad AMI AF: 0.718

Gnomad AMR AF: 0.739

Gnomad ASJ AF: 0.599

Gnomad EAS AF: 0.760

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.668

Gnomad MID AF: 0.656

Gnomad NFE AF: 0.636

Gnomad OTH AF: 0.683

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

GnomAD4 genome AF: 0.667 AC: 101191 AN: 151740 Hom.: 34058 Cov.: 33 AF XY: 0.665 AC XY: 49274 AN XY: 74134

Gnomad4 AFR AF: 0.711

Gnomad4 AMR AF: 0.739

Gnomad4 ASJ AF: 0.599

Gnomad4 EAS AF: 0.760

Gnomad4 SAS AF: 0.427

Gnomad4 FIN AF: 0.668

Gnomad4 NFE AF: 0.636

Gnomad4 OTH AF: 0.684

Alfa AF: 0.584 Hom.: 3438

Bravo AF: 0.688

Asia WGS AF: 0.625 AC: 2173 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.31
DANN	Benign	0.46

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: rs1871977; hg19: chr15-101863135; COSMIC: COSV61851791; COSMIC: COSV61851791;