Genetic Variant PCSK6:c.*161G>A (chr15-101347562-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_138324.3(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
NM_138324.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.787

Variant links:

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]

PCSK6 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
PCSK6	NM_002570.5 link	c.1859-15531G>A		intron_variant	Intron 13 of 21	ENST00000611716.5	NP_002561.1	P29122-1A2RQD9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK6	ENST00000611716.5 link	c.1859-15531G>A		intron_variant	Intron 13 of 21	1	NM_002570.5	ENSP00000482760.1		P29122-1

Frequencies

GnomAD3 genomes

AF:

0.458

AC:

69592

AN:

152028

Hom.:

16882

Cov.:

show subpopulations

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.:

AF XY:

0.518

AC XY:

315439

AN XY:

609110

show subpopulations

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.:

AF XY:

0.456

AC XY:

33895

AN XY:

74388

show subpopulations

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over