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
• Publications: 8 publications found

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]

PCSK5 Gene-Disease associations (from GenCC):

• syndromic congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372043.1. 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
	PCSK5	NM_001372043.1	MANE Select	c.2198-23C>T		intron	N/A	NP_001358972.1	A0A669KA35
	PCSK5	NM_001190482.2		c.2198-23C>T		intron	N/A	NP_001177411.1	Q92824-1
	PCSK5	NM_006200.6		c.2198-23C>T		intron	N/A	NP_006191.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK5	ENST00000674117.1	MANE Select	c.2198-23C>T		intron	N/A	ENSP00000500971.1	A0A669KA35
	PCSK5	ENST00000376752.9	TSL:1	c.2198-23C>T		intron	N/A	ENSP00000365943.4	Q92824-2
	PCSK5	ENST00000854198.1		c.2198-23C>T		intron	N/A	ENSP00000524257.1

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

African (AFR) AF: 0.995 AC: 31588 AN: 31750

American (AMR) AF: 0.987 AC: 43780 AN: 44360

Ashkenazi Jewish (ASJ) AF: 0.931 AC: 23772 AN: 25536

East Asian (EAS) AF: 1.00 AC: 39158 AN: 39168

South Asian (SAS) AF: 0.987 AC: 83004 AN: 84136

European-Finnish (FIN) AF: 0.977 AC: 50226 AN: 51394

Middle Eastern (MID) AF: 0.952 AC: 5321 AN: 5592

European-Non Finnish (NFE) AF: 0.970 AC: 1010810 AN: 1041698

Other (OTH) 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

African (AFR) AF: 0.993 AC: 41276 AN: 41578

American (AMR) AF: 0.984 AC: 15057 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.928 AC: 3221 AN: 3470

East Asian (EAS) AF: 0.999 AC: 5172 AN: 5176

South Asian (SAS) AF: 0.989 AC: 4775 AN: 4828

European-Finnish (FIN) AF: 0.979 AC: 10390 AN: 10618

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.968 AC: 65866 AN: 68040

Other (OTH) AF: 0.974 AC: 2058 AN: 2114

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	8.5
DANN	Benign	0.76
PhyloP100		0.65
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: rs1537183; hg19: chr9-78799566;