rs6235

Positions:

• chr5-96393194-C-G

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.2069G>C​(p.Ser690Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 1,613,804 control chromosomes in the GnomAD database, including 57,039 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 0.23 (4376 hom., cov: 32)
  • Exomes 𝑓: 0.27 (52663 hom.)
• Consequence: PCSK1 NM_000439.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.04

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=0.0042052567).
• BP6: Variant 5-96393194-C-G is Benign according to our data. Variant chr5-96393194-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 354639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-96393194-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK1	NM_000439.5	c.2069G>C	p.Ser690Thr	missense_variant	14/14	ENST00000311106.8	NP_000430.3
LOC101929710	NR_130776.1	n.354+13542C>G		intron_variant, non_coding_transcript_variant
PCSK1	NM_001177875.2	c.1928G>C	p.Ser643Thr	missense_variant	14/14		NP_001171346.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK1	ENST00000311106.8	c.2069G>C	p.Ser690Thr	missense_variant	14/14	1	NM_000439.5	ENSP00000308024	P1
PCSK1	ENST00000513085.1	n.1212G>C		non_coding_transcript_exon_variant	8/8	1
	ENST00000502645.2	n.354+13542C>G		intron_variant, non_coding_transcript_variant		5
PCSK1	ENST00000508626.5	c.1928G>C	p.Ser643Thr	missense_variant	14/14	2		ENSP00000421600

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35319 AN: 151932 Hom.: 4381 Cov.: 32

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.247

GnomAD3 exomes AF: 0.263 AC: 66025 AN: 251426 Hom.: 8949 AF XY: 0.268 AC XY: 36433 AN XY: 135888

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.198

Gnomad ASJ exome AF: 0.287

Gnomad EAS exome AF: 0.309

Gnomad SAS exome AF: 0.305

Gnomad FIN exome AF: 0.284

Gnomad NFE exome AF: 0.273

Gnomad OTH exome AF: 0.258

GnomAD4 exome AF: 0.266 AC: 389239 AN: 1461754 Hom.: 52663 Cov.: 35 AF XY: 0.268 AC XY: 194699 AN XY: 727184

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.197

Gnomad4 ASJ exome AF: 0.293

Gnomad4 EAS exome AF: 0.264

Gnomad4 SAS exome AF: 0.303

Gnomad4 FIN exome AF: 0.285

Gnomad4 NFE exome AF: 0.269

Gnomad4 OTH exome AF: 0.263

GnomAD4 genome AF: 0.232 AC: 35311 AN: 152050 Hom.: 4376 Cov.: 32 AF XY: 0.232 AC XY: 17233 AN XY: 74306

Gnomad4 AFR AF: 0.155

Gnomad4 AMR AF: 0.202

Gnomad4 ASJ AF: 0.279

Gnomad4 EAS AF: 0.309

Gnomad4 SAS AF: 0.308

Gnomad4 FIN AF: 0.278

Gnomad4 NFE AF: 0.266

Gnomad4 OTH AF: 0.246

Alfa AF: 0.263 Hom.: 4040

Bravo AF: 0.227

TwinsUK AF: 0.272 AC: 1007

ALSPAC AF: 0.287 AC: 1107

ESP6500AA AF: 0.159 AC: 702

ESP6500EA AF: 0.278 AC: 2389

ExAC AF: 0.265 AC: 32196

Asia WGS AF: 0.278 AC: 967 AN: 3478

EpiCase AF: 0.268

EpiControl AF: 0.276

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

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:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2021	This variant is associated with the following publications: (PMID: 24932808, 25625282, 24140494) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.45	T;T
MetaRNN	Benign	0.0042	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.85	N;N
REVEL	Benign	0.16
Sift	Benign	0.19	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.0010	B;.
Vest4		0.052
MPC		0.25
ClinPred		0.00042	T
GERP RS		4.0
Varity_R		0.11
gMVP		0.20

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: rs6235; hg19: chr5-95728898; COSMIC: COSV60735309;