Genetic Variant PCSK6:p.Val503Ala (chr15-101382116-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_002570.5(PCSK6):c.1508T>C(p.Val503Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 34)

Consequence

PCSK6
NM_002570.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.63

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15332177).

BP6

Variant 15-101382116-A-G is Benign according to our data. Variant chr15-101382116-A-G is described in ClinVar as Benign. ClinVar VariationId is 403287.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002570.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCSK6	NM_002570.5	MANE Select	c.1508T>C	p.Val503Ala	missense	Exon 11 of 22	NP_002561.1
PCSK6	NM_138319.4		c.1508T>C	p.Val503Ala	missense	Exon 11 of 21	NP_612192.1
PCSK6	NM_138325.4		c.1508T>C	p.Val503Ala	missense	Exon 11 of 14	NP_612198.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCSK6	ENST00000611716.5	TSL:1 MANE Select	c.1508T>C	p.Val503Ala	missense	Exon 11 of 22	ENSP00000482760.1
PCSK6	ENST00000622483.4	TSL:1	c.1508T>C	p.Val503Ala	missense	Exon 11 of 20	ENSP00000481556.1
PCSK6	ENST00000619160.4	TSL:1	c.1508T>C	p.Val503Ala	missense	Exon 11 of 19	ENSP00000482831.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.32

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.65

M_CAP

Benign

0.0064

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.4

PhyloP100

2.6

PrimateAI

Benign

0.37

REVEL

Benign

0.26

Sift4G

Benign

0.50

Polyphen

0.67

Vest4

0.45

MutPred

0.43

Gain of disorder (P = 0.0337)

MVP

0.40

ClinPred

0.19

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.077

gMVP

0.34

Mutation Taster

=86/14

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over