rs6232

chr5-96416081-T-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.661A>G(p.Asn221Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0451 in 1,612,350 control chromosomes in the GnomAD database, including 1,870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (103 hom., cov: 33)
  • Exomes 𝑓: 0.046 (1767 hom.)
• Consequence: PCSK1 NM_000439.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 5.67

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=0.012222022).
• BP6: Variant 5-96416081-T-C is Benign according to our data. Variant chr5-96416081-T-C is described in ClinVar as [Benign]. Clinvar id is 14040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-96416081-T-C is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK1	NM_000439.5	c.661A>G	p.Asn221Asp	missense_variant	6/14	ENST00000311106.8
LOC101929710	NR_130776.1	n.354+36429T>C		intron_variant, non_coding_transcript_variant
PCSK1	NM_001177875.2	c.520A>G	p.Asn174Asp	missense_variant	6/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK1	ENST00000311106.8	c.661A>G	p.Asn221Asp	missense_variant	6/14	1	NM_000439.5	P1
	ENST00000502645.2	n.354+36429T>C		intron_variant, non_coding_transcript_variant		5
PCSK1	ENST00000508626.5	c.520A>G	p.Asn174Asp	missense_variant	6/14	2

Frequencies

GnomAD3 genomes AF: 0.0322 AC: 4909 AN: 152228 Hom.: 105 Cov.: 33

Gnomad AFR AF: 0.00924

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0274

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0522

Gnomad FIN AF: 0.0247

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0499

Gnomad OTH AF: 0.0296

GnomAD3 exomes AF: 0.0386 AC: 9706 AN: 251438 Hom.: 252 AF XY: 0.0420 AC XY: 5702 AN XY: 135888

Gnomad AFR exome AF: 0.00818

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.0173

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0661

Gnomad FIN exome AF: 0.0309

Gnomad NFE exome AF: 0.0525

Gnomad OTH exome AF: 0.0370

GnomAD4 exome AF: 0.0465 AC: 67823 AN: 1460004 Hom.: 1767 Cov.: 29 AF XY: 0.0472 AC XY: 34289 AN XY: 726458

Gnomad4 AFR exome AF: 0.00792

Gnomad4 AMR exome AF: 0.0164

Gnomad4 ASJ exome AF: 0.0169

Gnomad4 EAS exome AF: 0.000479

Gnomad4 SAS exome AF: 0.0663

Gnomad4 FIN exome AF: 0.0336

Gnomad4 NFE exome AF: 0.0506

Gnomad4 OTH exome AF: 0.0389

GnomAD4 genome AF: 0.0322 AC: 4903 AN: 152346 Hom.: 103 Cov.: 33 AF XY: 0.0313 AC XY: 2331 AN XY: 74496

Gnomad4 AFR AF: 0.00921

Gnomad4 AMR AF: 0.0274

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.00173

Gnomad4 SAS AF: 0.0514

Gnomad4 FIN AF: 0.0247

Gnomad4 NFE AF: 0.0499

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0469 Hom.: 506

Bravo AF: 0.0316

TwinsUK AF: 0.0496 AC: 184

ALSPAC AF: 0.0589 AC: 227

ESP6500AA AF: 0.00999 AC: 44

ESP6500EA AF: 0.0501 AC: 431

ExAC AF: 0.0399 AC: 4842

Asia WGS AF: 0.0210 AC: 73 AN: 3478

EpiCase AF: 0.0505

EpiControl AF: 0.0507

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 18, 2018	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2021	This variant is associated with the following publications: (PMID: 31504391, 28271036, 18604207, 23383060, 22000902, 25784503, 19528091) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Body mass index quantitative trait locus 12 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Aug 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Uncertain	0.45
Sift	Benign	0.12	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.036	B;.
Vest4		0.080
MPC		0.30
ClinPred		0.031	T
GERP RS		6.1
Varity_R		0.61
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs6232; hg19: chr5-95751785; COSMIC: COSV60736739; COSMIC: COSV60736739;