15-101318331-C-T

Position:

• chr15-101318331-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002570.5(PCSK6):​c.2557G>A​(p.Gly853Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00665 in 1,558,158 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0049 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (40 hom.)
• Consequence: PCSK6 NM_002570.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.24

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008408874).
• BP6: Variant 15-101318331-C-T is Benign according to our data. Variant chr15-101318331-C-T is described in ClinVar as [Benign]. Clinvar id is 778105.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK6	NM_002570.5	c.2557G>A	p.Gly853Arg	missense_variant	19/22	ENST00000611716.5	NP_002561.1
PCSK6	NM_138319.4	c.2518G>A	p.Gly840Arg	missense_variant	18/21		NP_612192.1
PCSK6	NM_001291309.2	c.2335G>A	p.Gly779Arg	missense_variant	17/20		NP_001278238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK6	ENST00000611716.5	c.2557G>A	p.Gly853Arg	missense_variant	19/22	1	NM_002570.5	ENSP00000482760	A2

Frequencies

GnomAD3 genomes AF: 0.00493 AC: 750 AN: 152214 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00288

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00781

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00779

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00426 AC: 715 AN: 167884 Hom.: 4 AF XY: 0.00416 AC XY: 371 AN XY: 89206

Gnomad AFR exome AF: 0.00192

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000513

Gnomad SAS exome AF: 0.000173

Gnomad FIN exome AF: 0.00627

Gnomad NFE exome AF: 0.00745

Gnomad OTH exome AF: 0.00325

GnomAD4 exome AF: 0.00683 AC: 9606 AN: 1405826 Hom.: 40 Cov.: 30 AF XY: 0.00663 AC XY: 4599 AN XY: 694052

Gnomad4 AFR exome AF: 0.00101

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.0000396

Gnomad4 EAS exome AF: 0.0113

Gnomad4 SAS exome AF: 0.000101

Gnomad4 FIN exome AF: 0.00768

Gnomad4 NFE exome AF: 0.00774

Gnomad4 OTH exome AF: 0.00553

GnomAD4 genome AF: 0.00492 AC: 750 AN: 152332 Hom.: 2 Cov.: 33 AF XY: 0.00489 AC XY: 364 AN XY: 74488

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00289

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00781

Gnomad4 NFE AF: 0.00779

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00646 Hom.: 8

Bravo AF: 0.00456

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00121 AC: 5

ESP6500EA AF: 0.00578 AC: 48

ExAC AF: 0.00327 AC: 373

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	13
DANN	Benign	0.91
DEOGEN2	Benign	0.13	T;T;.;T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.59	T;T;T;T;T;T
MetaRNN	Benign	0.0084	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.80	N;.;.;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.45	.;N;.;.;.;.
REVEL	Uncertain	0.35
Sift	Benign	0.46	.;T;.;.;.;.
Sift4G	Benign	0.51	T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.
Vest4		0.18
MutPred		0.32		Loss of catalytic residue at V856 (P = 0.1415);.;.;.;Loss of catalytic residue at V856 (P = 0.1415);.;
MVP		0.31
ClinPred		0.011	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.062
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs45482895; hg19: chr15-101858536; COSMIC: COSV105260240; COSMIC: COSV105260240;