5-96401410-T-C

Variant names:

• chr5-96401410-T-C
• rs271921
• NM_000439.5:c.1197-1224A>G

Variant summary

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

The NM_000439.5(PCSK1):​c.1197-1224A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.704 in 152,130 control chromosomes in the GnomAD database, including 38,962 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 0.70 (38962 hom., cov: 32)
• Consequence: PCSK1 NM_000439.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.335
• Publications: 3 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.885 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.1197-1224A>G		intron	N/A	NP_000430.3
	CAST	NM_001423250.1		c.-175+21758T>C		intron	N/A	NP_001410179.1	P20810-1
	PCSK1	NM_001177875.2		c.1056-1224A>G		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.1197-1224A>G		intron	N/A	ENSP00000308024.2	P29120-1
	PCSK1	ENST00000513085.1	TSL:1	n.340-1224A>G		intron	N/A
	PCSK1	ENST00000947120.1		c.1197-1224A>G		intron	N/A	ENSP00000617179.1

Frequencies

GnomAD3 genomes AF: 0.704 AC: 106981 AN: 152012 Hom.: 38917 Cov.: 32

Gnomad AFR AF: 0.893

Gnomad AMI AF: 0.518

Gnomad AMR AF: 0.683

Gnomad ASJ AF: 0.714

Gnomad EAS AF: 0.592

Gnomad SAS AF: 0.606

Gnomad FIN AF: 0.496

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.713

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

GnomAD4 genome AF: 0.704 AC: 107076 AN: 152130 Hom.: 38962 Cov.: 32 AF XY: 0.696 AC XY: 51772 AN XY: 74366

African (AFR) AF: 0.893 AC: 37066 AN: 41516

American (AMR) AF: 0.682 AC: 10438 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.714 AC: 2476 AN: 3470

East Asian (EAS) AF: 0.592 AC: 3055 AN: 5160

South Asian (SAS) AF: 0.605 AC: 2916 AN: 4818

European-Finnish (FIN) AF: 0.496 AC: 5248 AN: 10576

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.643 AC: 43704 AN: 67986

Other (OTH) AF: 0.716 AC: 1507 AN: 2106

Alfa AF: 0.677 Hom.: 4543

Bravo AF: 0.729

Asia WGS AF: 0.609 AC: 2123 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.5
DANN	Benign	0.69
PhyloP100		-0.34
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: rs271921; hg19: chr5-95737114;