chr15-101305277-G-A

Position:

chr15-101305277-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002570.5(PCSK6):c.2891C>T(p.Thr964Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00419 in 1,611,692 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 18 hom. )

Consequence

PCSK6
NM_002570.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.86

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:

SNRPA1-DT (HGNC:55431): (SNRPA1 divergent transcript)

SNRPA1-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015419096).

BP6

Variant 15-101305277-G-A is Benign according to our data. Variant chr15-101305277-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 788742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PCSK6	NM_002570.5 linkuse as main transcript	c.2891C>T	p.Thr964Met	missense_variant	22/22	ENST00000611716.5	NP_002561.1
SNRPA1-DT	XR_007064783.1 linkuse as main transcript	n.8798G>A		non_coding_transcript_exon_variant	2/2
PCSK6	NM_138319.4 linkuse as main transcript	c.2852C>T	p.Thr951Met	missense_variant	21/21		NP_612192.1
PCSK6	NM_001291309.2 linkuse as main transcript	c.2669C>T	p.Thr890Met	missense_variant	20/20		NP_001278238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK6	ENST00000611716.5 linkuse as main transcript	c.2891C>T	p.Thr964Met	missense_variant	22/22	1	NM_002570.5	ENSP00000482760	A2	P29122-1
SNRPA1-DT	ENST00000558838.1 linkuse as main transcript	n.2130G>A		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes

AF:

0.00296

AC:

451

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00405

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00504

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00321

AC:

788

AN:

245790

Hom.:

AF XY:

0.00336

AC XY:

449

AN XY:

133824

show subpopulations

Gnomad AFR exome

AF:

0.000395

Gnomad AMR exome

AF:

0.00125

Gnomad ASJ exome

AF:

0.00270

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00158

Gnomad FIN exome

AF:

0.00490

Gnomad NFE exome

AF:

0.00488

Gnomad OTH exome

AF:

0.00334

GnomAD4 exome

AF:

0.00432

AC:

6308

AN:

1459364

Hom.:

Cov.:

AF XY:

0.00438

AC XY:

3180

AN XY:

725982

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.00241

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00170

Gnomad4 FIN exome

AF:

0.00511

Gnomad4 NFE exome

AF:

0.00500

Gnomad4 OTH exome

AF:

0.00318

GnomAD4 genome

AF:

0.00295

AC:

450

AN:

152328

Hom.:

Cov.:

AF XY:

0.00267

AC XY:

199

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000601

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00260

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00405

Gnomad4 NFE

AF:

0.00504

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00429

Hom.:

Bravo

AF:

0.00284

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.000472

AC:

ESP6500EA

AF:

0.00461

AC:

ExAC

AF:

0.00334

AC:

404

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00463

EpiControl

AF:

0.00463

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 20, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

T;T;.;T

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.015

T;T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Uncertain

2.2

M;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.9

.;D;.;.

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

.;D;.;.

Sift4G

Uncertain

0.0060

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.58

MVP

0.80

ClinPred

0.012

GERP RS

5.0

Varity_R

0.29

gMVP

0.57

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over