5-96434194-G-C

Variant names:

• chr5-96434194-G-C
• rs155979

Variant summary

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

The variant allele was found at a frequency of 0.875 in 152,234 control chromosomes in the GnomAD database, including 58,451 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 0.87 (58439 hom., cov: 31)
  • Exomes 𝑓: 0.83 (12 hom.)
• Consequence: LOC102724070 intragenic
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.890
• Publications: 7 publications found

Genes affected

LOC102724070 (HGNC:):

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]

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 Gene-Disease associations (from GenCC):

• obesity due to prohormone convertase I deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

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 (AFR) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC102724070		n.96434194G>C		intragenic_variant
CAST	NM_001423250.1	c.-175+54542G>C		intron_variant	Intron 5 of 35		NP_001410179.1
CAST	NM_001423251.1	c.-175+54542G>C		intron_variant	Intron 5 of 34		NP_001410180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000718093.1	c.-175+54542G>C		intron_variant	Intron 3 of 30			ENSP00000520668.1
CAST	ENST00000718091.1	c.-175+54542G>C		intron_variant	Intron 3 of 11			ENSP00000520667.1
CAST	ENST00000718089.1	n.450-7701G>C		intron_variant	Intron 5 of 6

Frequencies

GnomAD3 genomes AF: 0.874 AC: 132990 AN: 152080 Hom.: 58389 Cov.: 31

Gnomad AFR AF: 0.943

Gnomad AMI AF: 0.902

Gnomad AMR AF: 0.815

Gnomad ASJ AF: 0.868

Gnomad EAS AF: 0.740

Gnomad SAS AF: 0.777

Gnomad FIN AF: 0.909

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.858

Gnomad OTH AF: 0.866

GnomAD4 exome AF: 0.833 AC: 30 AN: 36 Hom.: 12 AF XY: 0.786 AC XY: 22 AN XY: 28

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.800 AC: 24 AN: 30

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.875 AC: 133101 AN: 152198 Hom.: 58439 Cov.: 31 AF XY: 0.874 AC XY: 65065 AN XY: 74420

African (AFR) AF: 0.943 AC: 39163 AN: 41530

American (AMR) AF: 0.815 AC: 12450 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.868 AC: 3013 AN: 3472

East Asian (EAS) AF: 0.740 AC: 3819 AN: 5164

South Asian (SAS) AF: 0.776 AC: 3736 AN: 4816

European-Finnish (FIN) AF: 0.909 AC: 9641 AN: 10610

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.858 AC: 58368 AN: 68004

Other (OTH) AF: 0.867 AC: 1834 AN: 2116

Alfa AF: 0.845 Hom.: 3175

Bravo AF: 0.871

Asia WGS AF: 0.794 AC: 2762 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.1
DANN	Benign	0.61
PhyloP100		-0.89
PromoterAI		0.0054	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs155979; hg19: chr5-95769898; COSMIC: COSV60734467;