rs1537183

Variant names:

• chr9-76184650-C-T
• rs1537183
• NM_001372043.1:c.2198-23C>T

Variant summary

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

The NM_001372043.1(PCSK5):​c.2198-23C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.973 in 1,533,600 control chromosomes in the GnomAD database, including 726,449 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 0.98 (72897 hom., cov: 32)
  • Exomes 𝑓: 0.97 (653552 hom.)
• Consequence: PCSK5 NM_001372043.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.650

Genes affected

PCSK5 (HGNC:8747): (proprotein convertase subtilisin/kexin type 5) 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. It then sorts to the trans-Golgi network where a second autocatalytic event takes place and the catalytic activity is acquired. This encoded protein is widely expressed and one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. It mediates posttranslational endoproteolytic processing for several integrin alpha subunits and is thought to process prorenin, pro-membrane type-1 matrix metalloproteinase and HIV-1 glycoprotein gp160. Alternative splicing results in multiple transcript variants, some of which encode distinct isoforms, including a protease packaged into dense core granules (PC5A) and a type 1 membrane bound protease (PC5B). [provided by RefSeq, May 2014]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.985 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK5	NM_001372043.1	c.2198-23C>T		intron_variant	Intron 16 of 37	ENST00000674117.1	NP_001358972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK5	ENST00000674117.1	c.2198-23C>T		intron_variant	Intron 16 of 37		NM_001372043.1	ENSP00000500971.1
PCSK5	ENST00000376752.9	c.2198-23C>T		intron_variant	Intron 16 of 20	1		ENSP00000365943.4
PCSK5	ENST00000545128.5	c.2198-23C>T		intron_variant	Intron 16 of 36	5		ENSP00000446280.1
PCSK5	ENST00000424854.6	c.1217-23C>T		intron_variant	Intron 9 of 30	5		ENSP00000411654.1

Frequencies

GnomAD3 genomes AF: 0.978 AC: 148892 AN: 152212 Hom.: 72839 Cov.: 32

Gnomad AFR AF: 0.993

Gnomad AMI AF: 0.993

Gnomad AMR AF: 0.984

Gnomad ASJ AF: 0.928

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.989

Gnomad FIN AF: 0.979

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.968

Gnomad OTH AF: 0.973

GnomAD2 exomes AF: 0.976 AC: 239957 AN: 245790 AF XY: 0.976

Gnomad AFR exome AF: 0.996

Gnomad AMR exome AF: 0.988

Gnomad ASJ exome AF: 0.926

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.977

Gnomad NFE exome AF: 0.968

Gnomad OTH exome AF: 0.972

GnomAD4 exome AF: 0.973 AC: 1343533 AN: 1381270 Hom.: 653552 Cov.: 20 AF XY: 0.973 AC XY: 673093 AN XY: 691988

Gnomad4 AFR exome AF: 0.995 AC: 31588 AN: 31750

Gnomad4 AMR exome AF: 0.987 AC: 43780 AN: 44360

Gnomad4 ASJ exome AF: 0.931 AC: 23772 AN: 25536

Gnomad4 EAS exome AF: 1.00 AC: 39158 AN: 39168

Gnomad4 SAS exome AF: 0.987 AC: 83004 AN: 84136

Gnomad4 FIN exome AF: 0.977 AC: 50226 AN: 51394

Gnomad4 NFE exome AF: 0.970 AC: 1010810 AN: 1041698

Gnomad4 Remaining exome AF: 0.969 AC: 55874 AN: 57636

GnomAD4 genome AF: 0.978 AC: 149009 AN: 152330 Hom.: 72897 Cov.: 32 AF XY: 0.980 AC XY: 72964 AN XY: 74488

Gnomad4 AFR AF: 0.993 AC: 0.992737 AN: 0.992737

Gnomad4 AMR AF: 0.984 AC: 0.984118 AN: 0.984118

Gnomad4 ASJ AF: 0.928 AC: 0.928242 AN: 0.928242

Gnomad4 EAS AF: 0.999 AC: 0.999227 AN: 0.999227

Gnomad4 SAS AF: 0.989 AC: 0.989022 AN: 0.989022

Gnomad4 FIN AF: 0.979 AC: 0.978527 AN: 0.978527

Gnomad4 NFE AF: 0.968 AC: 0.968048 AN: 0.968048

Gnomad4 OTH AF: 0.974 AC: 0.97351 AN: 0.97351

Alfa AF: 0.967 Hom.: 23083

Bravo AF: 0.980

Asia WGS AF: 0.988 AC: 3431 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	8.5
DANN	Benign	0.76
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

Publications

LitVar

Other links and lift over

dbSNP: rs1537183; hg19: chr9-78799566;