Variant X-48831307-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_013271.5(PCSK1N):c.736G>C(p.Glu246Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,177,351 control chromosomes in the GnomAD database, including 1 homozygotes. There are 57 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., 5 hem., cov: 24)

Exomes 𝑓: 0.00015 ( 1 hom. 52 hem. )

Consequence

PCSK1N
NM_013271.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.13

Variant links:

Genes affected

PCSK1N (HGNC:17301): (proprotein convertase subtilisin/kexin type 1 inhibitor) The protein encoded by this gene functions as an inhibitor of prohormone convertase 1, which regulates the proteolytic cleavage of neuroendocrine peptide precursors. The proprotein is further processed into multiple short peptides. A polymorphism within this gene may be associated with obesity. [provided by RefSeq, Aug 2013]

PCSK1N links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a mutagenesis_site Reduces inhibition of PCSK1. (size 0) in uniprot entity PCS1N_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.12743264).

BS2

High Hemizygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK1N	NM_013271.5 linkuse as main transcript	c.736G>C	p.Glu246Gln	missense_variant	3/3	ENST00000218230.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK1N	ENST00000218230.6 linkuse as main transcript	c.736G>C	p.Glu246Gln	missense_variant	3/3	1	NM_013271.5	P1

Frequencies

GnomAD3 genomes

AF:

0.000116

AC:

AN:

112457

Hom.:

Cov.:

AF XY:

0.000144

AC XY:

AN XY:

34635

show subpopulations

Gnomad AFR

AF:

0.0000322

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00189

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000111

AC:

AN:

117280

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

29162

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000425

Gnomad ASJ exome

AF:

0.00106

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000109

Gnomad OTH exome

AF:

0.000325

GnomAD4 exome

AF:

0.000153

AC:

163

AN:

1064894

Hom.:

Cov.:

AF XY:

0.000152

AC XY:

AN XY:

342108

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000303

Gnomad4 ASJ exome

AF:

0.00185

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000143

Gnomad4 OTH exome

AF:

0.000223

GnomAD4 genome

AF:

0.000116

AC:

AN:

112457

Hom.:

Cov.:

AF XY:

0.000144

AC XY:

AN XY:

34635

show subpopulations

Gnomad4 AFR

AF:

0.0000322

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00189

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000364

Hom.:

Bravo

AF:

0.000147

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000172

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The c.736G>C (p.E246Q) alteration is located in exon 3 (coding exon 3) of the PCSK1N gene. This alteration results from a G to C substitution at nucleotide position 736, causing the glutamic acid (E) at amino acid position 246 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.55

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.63

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.0

MutationTaster

Benign

0.99

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.3

REVEL

Benign

0.12

Sift

Uncertain

0.013

Sift4G

Benign

0.13

Polyphen

0.97

Vest4

0.37

MutPred

0.093

Gain of MoRF binding (P = 0.0244);

MVP

0.46

MPC

1.9

ClinPred

0.17

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.27

gMVP

0.050

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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