NM_000439.5:c.*1530T>C

Variant names:

• chr5-96391471-A-G
• rs2882298
• NM_000439.5:c.*1530T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000439.5(PCSK1):​c.*1530T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 152,102 control chromosomes in the GnomAD database, including 7,246 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7245 hom., cov: 32)
  • Exomes 𝑓: 1.0 (1 hom.)
• Consequence: PCSK1 NM_000439.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.46
• Publications: 7 publications found

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]

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, G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

CAST (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 5-96391471-A-G is Benign according to our data. Variant chr5-96391471-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 354617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000439.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK1	NM_000439.5	MANE Select	c.*1530T>C		3_prime_UTR	Exon 14 of 14	NP_000430.3
	PCSK1	NM_001177875.2		c.*1530T>C		3_prime_UTR	Exon 14 of 14	NP_001171346.1	P29120-2
	CAST	NM_001423250.1		c.-175+11819A>G		intron	N/A	NP_001410179.1	P20810-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK1	ENST00000311106.8	TSL:1 MANE Select	c.*1530T>C		3_prime_UTR	Exon 14 of 14	ENSP00000308024.2	P29120-1
	PCSK1	ENST00000947120.1		c.*1530T>C		3_prime_UTR	Exon 14 of 14	ENSP00000617179.1
	PCSK1	ENST00000914384.1		c.*1530T>C		3_prime_UTR	Exon 13 of 13	ENSP00000584443.1

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46253 AN: 151982 Hom.: 7249 Cov.: 32

Gnomad AFR AF: 0.371

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.312

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.293

GnomAD4 exome AF: 1.00 AC: 2 AN: 2 Hom.: 1 Cov.: 0 AF XY: 1.00 AC XY: 2 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 2 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.304 AC: 46259 AN: 152100 Hom.: 7245 Cov.: 32 AF XY: 0.301 AC XY: 22395 AN XY: 74358

African (AFR) AF: 0.370 AC: 15346 AN: 41472

American (AMR) AF: 0.224 AC: 3427 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 989 AN: 3464

East Asian (EAS) AF: 0.311 AC: 1612 AN: 5184

South Asian (SAS) AF: 0.310 AC: 1494 AN: 4820

European-Finnish (FIN) AF: 0.304 AC: 3214 AN: 10568

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.285 AC: 19350 AN: 67984

Other (OTH) AF: 0.291 AC: 615 AN: 2110

Alfa AF: 0.297 Hom.: 1393

Bravo AF: 0.306

Asia WGS AF: 0.292 AC: 1016 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Monogenic Non-Syndromic Obesity (1)
-	-	1	not provided (1)
-	-	1	Obesity due to prohormone convertase I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.9
DANN	Benign	0.83
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2882298; hg19: chr5-95727175;