5-96397408-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000439.5(PCSK1):c.1650T>C(p.Asn550Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 1,610,164 control chromosomes in the GnomAD database, including 112,577 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 11019 hom., cov: 32)

Exomes 𝑓: 0.37 ( 101558 hom. )

Consequence

PCSK1
NM_000439.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.23

Publications

25 publications found

Variant links:

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]

PCSK1 links:

CAST (HGNC:1515): (calpastatin) The protein encoded by this gene is an endogenous calpain (calcium-dependent cysteine protease) inhibitor. It consists of an N-terminal domain L and four repetitive calpain-inhibition domains (domains 1-4), and it is involved in the proteolysis of amyloid precursor protein. The calpain/calpastatin system is involved in numerous membrane fusion events, such as neural vesicle exocytosis and platelet and red-cell aggregation. The encoded protein is also thought to affect the expression levels of genes encoding structural or regulatory proteins. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2010]

CAST Gene-Disease associations (from GenCC):

peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp

CAST links:

CAST (HGNC:):

CAST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 5-96397408-A-G is Benign according to our data. Variant chr5-96397408-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 354643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.23 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK1	NM_000439.5 link	c.1650T>C	p.Asn550Asn	synonymous_variant	Exon 12 of 14	ENST00000311106.8	NP_000430.3	P29120-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK1	ENST00000311106.8 link	c.1650T>C	p.Asn550Asn	synonymous_variant	Exon 12 of 14	1	NM_000439.5	ENSP00000308024.2		P29120-1

Frequencies

GnomAD3 genomes

AF:

0.376

AC:

57070

AN:

151892

Hom.:

11014

Cov.:

show subpopulations

Gnomad AFR

AF:

0.418

Gnomad AMI

AF:

0.362

Gnomad AMR

AF:

0.447

Gnomad ASJ

AF:

0.409

Gnomad EAS

AF:

0.274

Gnomad SAS

AF:

0.283

Gnomad FIN

AF:

0.216

Gnomad MID

AF:

0.380

Gnomad NFE

AF:

0.371

Gnomad OTH

AF:

0.397

GnomAD2 exomes

AF:

0.358

AC:

89902

AN:

251166

AF XY:

0.352

show subpopulations

Gnomad AFR exome

AF:

0.417

Gnomad AMR exome

AF:

0.468

Gnomad ASJ exome

AF:

0.426

Gnomad EAS exome

AF:

0.268

Gnomad FIN exome

AF:

0.218

Gnomad NFE exome

AF:

0.368

Gnomad OTH exome

AF:

0.365

GnomAD4 exome

AF:

0.370

AC:

538956

AN:

1458154

Hom.:

101558

Cov.:

AF XY:

0.368

AC XY:

266682

AN XY:

725638

show subpopulations

African (AFR)

AF:

0.419

AC:

14009

AN:

33398

American (AMR)

AF:

0.458

AC:

20487

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.413

AC:

10771

AN:

26102

East Asian (EAS)

AF:

0.299

AC:

11845

AN:

39650

South Asian (SAS)

AF:

0.297

AC:

25617

AN:

86176

European-Finnish (FIN)

AF:

0.225

AC:

12040

AN:

53404

Middle Eastern (MID)

AF:

0.425

AC:

2449

AN:

5760

European-Non Finnish (NFE)

AF:

0.378

AC:

419370

AN:

1108686

Other (OTH)

AF:

0.371

AC:

22368

AN:

60262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

15767

31534

47300

63067

78834

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13252

26504

39756

53008

66260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.376

AC:

57101

AN:

152010

Hom.:

11019

Cov.:

AF XY:

0.371

AC XY:

27570

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.417

AC:

17282

AN:

41434

American (AMR)

AF:

0.446

AC:

6811

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.409

AC:

1419

AN:

3466

East Asian (EAS)

AF:

0.275

AC:

1423

AN:

5176

South Asian (SAS)

AF:

0.282

AC:

1360

AN:

4816

European-Finnish (FIN)

AF:

0.216

AC:

2289

AN:

10582

Middle Eastern (MID)

AF:

0.371

AC:

109

AN:

294

European-Non Finnish (NFE)

AF:

0.371

AC:

25230

AN:

67942

Other (OTH)

AF:

0.401

AC:

848

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1845

3689

5534

7378

9223

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

558

1116

1674

2232

2790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.388

Hom.:

19441

Bravo

AF:

0.395

Asia WGS

AF:

0.280

AC:

978

AN:

3476

EpiCase

AF:

0.383

EpiControl

AF:

0.379

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Obesity due to prohormone convertase I deficiency

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Monogenic Non-Syndromic Obesity

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

3.7

(source)

DANN

Benign

0.73

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over