rs271924

Variant names:

• chr5-96401720-A-T
• rs271924
• NM_000439.5:c.1197-1534T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000439.5(PCSK1):​c.1197-1534T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 151,880 control chromosomes in the GnomAD database, including 8,448 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.33 (8448 hom., cov: 31)
• Consequence: PCSK1 NM_000439.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.423 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.1197-1534T>A		intron	N/A	NP_000430.3
	CAST	NM_001423250.1		c.-175+22068A>T		intron	N/A	NP_001410179.1	P20810-1
	PCSK1	NM_001177875.2		c.1056-1534T>A		intron	N/A	NP_001171346.1	P29120-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK1	ENST00000311106.8	TSL:1 MANE Select	c.1197-1534T>A		intron	N/A	ENSP00000308024.2	P29120-1
	PCSK1	ENST00000513085.1	TSL:1	n.340-1534T>A		intron	N/A
	PCSK1	ENST00000947120.1		c.1197-1534T>A		intron	N/A	ENSP00000617179.1

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49366 AN: 151760 Hom.: 8443 Cov.: 31

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.432

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.365

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.325 AC: 49382 AN: 151880 Hom.: 8448 Cov.: 31 AF XY: 0.322 AC XY: 23930 AN XY: 74216

African (AFR) AF: 0.241 AC: 9979 AN: 41432

American (AMR) AF: 0.431 AC: 6583 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 1421 AN: 3470

East Asian (EAS) AF: 0.273 AC: 1404 AN: 5152

South Asian (SAS) AF: 0.280 AC: 1342 AN: 4790

European-Finnish (FIN) AF: 0.216 AC: 2281 AN: 10560

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.370 AC: 25154 AN: 67904

Other (OTH) AF: 0.370 AC: 780 AN: 2110

Alfa AF: 0.340 Hom.: 1119

Bravo AF: 0.338

Asia WGS AF: 0.270 AC: 942 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.96
DANN	Benign	0.54
PhyloP100		-1.2
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: rs271924; hg19: chr5-95737424;