9-76071902-G-T

Variant names:

• chr9-76071902-G-T
• rs2297344
• NM_001372043.1:c.894+4G>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.894+4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,612,676 control chromosomes in the GnomAD database, including 25,120 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2087 hom., cov: 32)
  • Exomes 𝑓: 0.18 (23033 hom.)
• Consequence: PCSK5 NM_001372043.1 splice_region, intron
• Scores: Splicing: ADA: 0.0001574
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.264
• 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=-0.5).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.217 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.894+4G>T		splice_region intron	N/A	NP_001358972.1	A0A669KA35
	PCSK5	NM_001190482.2		c.894+4G>T		splice_region intron	N/A	NP_001177411.1	Q92824-1
	PCSK5	NM_006200.6		c.894+4G>T		splice_region 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.894+4G>T		splice_region intron	N/A	ENSP00000500971.1	A0A669KA35
	PCSK5	ENST00000376752.9	TSL:1	c.894+4G>T		splice_region intron	N/A	ENSP00000365943.4	Q92824-2
	PCSK5	ENST00000854198.1		c.894+4G>T		splice_region intron	N/A	ENSP00000524257.1

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24868 AN: 152066 Hom.: 2089 Cov.: 32

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.161

GnomAD2 exomes AF: 0.166 AC: 41159 AN: 248586 AF XY: 0.169

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.0844

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.228

Gnomad FIN exome AF: 0.191

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.168

GnomAD4 exome AF: 0.176 AC: 256535 AN: 1460490 Hom.: 23033 Cov.: 31 AF XY: 0.177 AC XY: 128315 AN XY: 726516

African (AFR) AF: 0.137 AC: 4594 AN: 33440

American (AMR) AF: 0.0892 AC: 3977 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 3909 AN: 26070

East Asian (EAS) AF: 0.233 AC: 9234 AN: 39682

South Asian (SAS) AF: 0.174 AC: 14943 AN: 86120

European-Finnish (FIN) AF: 0.189 AC: 10107 AN: 53388

Middle Eastern (MID) AF: 0.147 AC: 844 AN: 5754

European-Non Finnish (NFE) AF: 0.179 AC: 198566 AN: 1111112

Other (OTH) AF: 0.172 AC: 10361 AN: 60324

GnomAD4 genome AF: 0.163 AC: 24877 AN: 152186 Hom.: 2087 Cov.: 32 AF XY: 0.164 AC XY: 12219 AN XY: 74396

African (AFR) AF: 0.137 AC: 5688 AN: 41514

American (AMR) AF: 0.123 AC: 1888 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 527 AN: 3470

East Asian (EAS) AF: 0.228 AC: 1179 AN: 5172

South Asian (SAS) AF: 0.166 AC: 797 AN: 4814

European-Finnish (FIN) AF: 0.190 AC: 2017 AN: 10608

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.181 AC: 12299 AN: 67998

Other (OTH) AF: 0.158 AC: 334 AN: 2116

Alfa AF: 0.172 Hom.: 4559

Bravo AF: 0.157

Asia WGS AF: 0.189 AC: 653 AN: 3478

EpiCase AF: 0.178

EpiControl AF: 0.179

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.81
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.038
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: rs2297344; hg19: chr9-78686818; COSMIC: COSV65085543;