rs6234

chr5-96393270-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000439.5(PCSK1):c.1993C>G(p.Gln665Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 1,613,634 control chromosomes in the GnomAD database, including 57,709 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4653 hom., cov: 32)
  • Exomes 𝑓: 0.27 (53056 hom.)
• Consequence: PCSK1 NM_000439.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.110

Genes affected

PCSK1 (HGNC:8743): (proprotein convertase subtilisin/kexin type 1) 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 subcellular compartments where a second autocatalytic even takes place and the catalytic activity is acquired. The protease is packaged into and activated in dense core secretory granules and expressed in the neuroendocrine system and brain. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. It functions in the proteolytic activation of polypeptide hormones and neuropeptides precursors. Mutations in this gene have been associated with susceptibility to obesity and proprotein convertase 1/3 deficiency. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene [provided by RefSeq, Jan 2014]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003394097).
• BP6: Variant 5-96393270-G-C is Benign according to our data. Variant chr5-96393270-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 354640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-96393270-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK1	NM_000439.5	c.1993C>G	p.Gln665Glu	missense_variant	14/14	ENST00000311106.8
LOC101929710	NR_130776.1	n.354+13618G>C		intron_variant, non_coding_transcript_variant
PCSK1	NM_001177875.2	c.1852C>G	p.Gln618Glu	missense_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK1	ENST00000311106.8	c.1993C>G	p.Gln665Glu	missense_variant	14/14	1	NM_000439.5	P1
PCSK1	ENST00000513085.1	n.1136C>G		non_coding_transcript_exon_variant	8/8	1
	ENST00000502645.2	n.354+13618G>C		intron_variant, non_coding_transcript_variant		5
PCSK1	ENST00000508626.5	c.1852C>G	p.Gln618Glu	missense_variant	14/14	2

Frequencies

GnomAD3 genomes AF: 0.243 AC: 36901 AN: 151924 Hom.: 4658 Cov.: 32

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.251

GnomAD3 exomes AF: 0.266 AC: 66704 AN: 251072 Hom.: 9079 AF XY: 0.271 AC XY: 36700 AN XY: 135674

Gnomad AFR exome AF: 0.188

Gnomad AMR exome AF: 0.200

Gnomad ASJ exome AF: 0.287

Gnomad EAS exome AF: 0.308

Gnomad SAS exome AF: 0.308

Gnomad FIN exome AF: 0.285

Gnomad NFE exome AF: 0.274

Gnomad OTH exome AF: 0.258

GnomAD4 exome AF: 0.268 AC: 391365 AN: 1461592 Hom.: 53056 Cov.: 36 AF XY: 0.269 AC XY: 195692 AN XY: 727100

Gnomad4 AFR exome AF: 0.183

Gnomad4 AMR exome AF: 0.199

Gnomad4 ASJ exome AF: 0.292

Gnomad4 EAS exome AF: 0.263

Gnomad4 SAS exome AF: 0.305

Gnomad4 FIN exome AF: 0.285

Gnomad4 NFE exome AF: 0.269

Gnomad4 OTH exome AF: 0.265

GnomAD4 genome AF: 0.243 AC: 36892 AN: 152042 Hom.: 4653 Cov.: 32 AF XY: 0.242 AC XY: 17999 AN XY: 74304

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.205

Gnomad4 ASJ AF: 0.279

Gnomad4 EAS AF: 0.307

Gnomad4 SAS AF: 0.310

Gnomad4 FIN AF: 0.278

Gnomad4 NFE AF: 0.267

Gnomad4 OTH AF: 0.250

Alfa AF: 0.265 Hom.: 4212

Bravo AF: 0.238

TwinsUK AF: 0.272 AC: 1009

ALSPAC AF: 0.288 AC: 1109

ESP6500AA AF: 0.193 AC: 849

ESP6500EA AF: 0.279 AC: 2397

ExAC AF: 0.269 AC: 32618

Asia WGS AF: 0.280 AC: 973 AN: 3478

EpiCase AF: 0.269

EpiControl AF: 0.276

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 19, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2021	This variant is associated with the following publications: (PMID: 28271036, 23383060, 25625282, 24932808) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Monogenic Non-Syndromic Obesity Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Obesity due to prohormone convertase I deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.062
Dann	Benign	0.60
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.016	T;T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.13	N;N
REVEL	Benign	0.081
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.011
MPC		0.28
ClinPred		0.0016	T
GERP RS		-0.27
Varity_R		0.031
gMVP		0.11

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

Other links and lift over

dbSNP: rs6234; hg19: chr5-95728974; COSMIC: COSV60735461;